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Nayerpour Dizaj T, Doustmihan A, Sadeghzadeh Oskouei B, Akbari M, Jaymand M, Mazloomi M, Jahanban-Esfahlan R. Significance of PSCA as a novel prognostic marker and therapeutic target for cancer. Cancer Cell Int 2024; 24:135. [PMID: 38627732 PMCID: PMC11020972 DOI: 10.1186/s12935-024-03320-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Accepted: 03/30/2024] [Indexed: 04/20/2024] Open
Abstract
One of the contributing factors in the diagnosis and treatment of most cancers is the identification of their surface antigens. Cancer tissues or cells have their specific antigens. Some antigens that are present in many cancers elicit different functions. One of these antigens is the prostate stem cell antigen (PSCA) antigen, which was first identified in the prostate. PSCA is a cell surface protein that has different functions in different tissues. It can play an inhibitory role in cell proliferation as well as a tumor-inducing role. PSCA has several genetic variants involved in cancer susceptibility in some tissues, so identifying the characteristics of this antigen and its relationship with clinical features can provide more information on diagnosis and treatment of patients with cancers. Most studies on the PSCA have focused on prostate cancer. While it is also expressed in other cancers, little attention has been paid to its role as a valuable diagnostic, prognostic, and therapeutic tool in other cancers. PSCA has several genetic variants that seem to play a significant role in cancer susceptibility in some tissues, so identifying the characteristics of this antigen and its relationship and variants with clinical features can be beneficial in concomitant cancer therapy and diagnosis, as theranostic tools. In this study, we will review the alteration of the PSCA expression and its polymorphisms and evaluate its clinical and theranostics significance in various cancers.
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Affiliation(s)
- Tina Nayerpour Dizaj
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Abolfazl Doustmihan
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behnaz Sadeghzadeh Oskouei
- Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Morteza Akbari
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Jaymand
- Nano Drug Delivery Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - MirAhmad Mazloomi
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Rana Jahanban-Esfahlan
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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Wang XF, Liu DL, Geng L. The PSCA rs2294008 (C/T) Polymorphism Increases the Risk of Gastric and Bladder Cancer: A Meta-Analysis. Genet Test Mol Biomarkers 2023; 27:44-55. [PMID: 36853840 DOI: 10.1089/gtmb.2022.0067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2023] Open
Abstract
Background: It has been reported that prostate stem cell antigen (PSCA) is overexpressed in certain cancer types and confers poor prognoses. The rs2294008 (C/T) polymorphism of PSCA is considered to be associated with risk for gastric, bladder, and colorectal cancers; however, these studies have produced inconsistent results, so we performed this meta-analysis to verify the association between the PSCA rs2294008 (C/T) polymorphism and cancer risk. Methods: A systematic literature search was performed using PubMed, EMBASE, and the Chinese National Knowledge Infrastructure, through October 20, 2022 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association between the PSCA rs2294008 (C/T) polymorphism and cancer risk. In addition, we explored PSCA mRNA expression in cancers through online databases. Results: In total, 45 articles met our inclusion criteria and were analyzed, including 37,586 cancer cases and 51,197 non-cancer controls. Except in the recessive model, the pooled effect indicated the PSCA rs2294008 T allele was associated with an increased overall cancer risk (T vs. C: OR = 1.120, 95% CI = 1.056-1.188, p < 0.01; TT vs. CC: OR = 1.206, 95% CI = 1.066-1.364, p = 0.03; CT vs. CC: OR = 1.249, 95% CI = 1.151-1.356, p < 0.01; [CT+TT] vs. CC: OR = 1.248, 95% CI = 1.147-1.359, p < 0.01; TT vs. [CT+CC]: OR = 1.051, 95% CI = 0.954-1.156, p = 0.314). In the subgroup analysis, there were significant associations between the rs2294008 T allele and increased risk of bladder and gastric cancer. Two different online tools were used to explore the PSCA mRNA levels in cancer and the corresponding normal adjacent tissues. We found that expression of PSCA was significantly lower in gastric cancer patients. Conclusions: The PSCA rs2294008 T polymorphism is related to increased cancer susceptibility, especially for gastric and bladder cancers. This polymorphism results in a decreased PSCA expression level in gastric cancer.
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Affiliation(s)
- Xiao-Feng Wang
- Department of Medical Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Dong-Li Liu
- Key Laboratory of Carcinogenesis and Cancer Invasion, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Ministry of Education, Shanghai, China
| | - Li Geng
- Department of Medical Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Lam SY, Mommersteeg MC, Yu B, Broer L, Spaander MCW, Frost F, Weiss S, Völzke H, Lerch MM, Schöttker B, Zhang Y, Stocker H, Brenner H, Levy D, Hwang SJ, Wood AC, Rich SS, Rotter JI, Taylor KD, Tracy RP, Kabagambe EK, Leja M, Klovins J, Peculis R, Rudzite D, Nikitina-Zake L, Skenders G, Rovite V, Uitterlinden A, Kuipers EJ, Fuhler GM, Homuth G, Peppelenbosch MP. Toll-Like Receptor 1 Locus Re-examined in a Genome-Wide Association Study Update on Anti-Helicobacter pylori IgG Titers. Gastroenterology 2022; 162:1705-1715. [PMID: 35031300 PMCID: PMC11734630 DOI: 10.1053/j.gastro.2022.01.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 12/03/2021] [Accepted: 01/07/2022] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS A genome-wide significant association between anti-Helicobacter pylori (H pylori) IgG titers and Toll-like receptor (TLR1/6/10) locus on 4p14 was demonstrated for individuals of European ancestry, but not uniformly replicated. We re-investigated this association in an updated genome-wide association study (GWAS) meta-analysis for populations with low gastric cancer incidence, address potential causes of cohort heterogeneity, and explore functional implications of genetic variation at the TLR1/6/10 locus. METHODS The dichotomous GWAS (25% individuals exhibiting highest anti-H pylori IgG titers vs remaining 75%) included discovery and replication sampls of, respectively, n = 15,685 and n = 9676, all of European ancestry. Longitudinal analysis of serologic data was performed on H pylori-eradicated subjects (n = 132) and patients under surveillance for premalignant gastric lesions (n = 107). TLR1/6/10 surface expression, TLR1 mRNA, and cytokine levels were measured in leukocyte subsets of healthy subjects (n = 26) genotyped for TLR1/6/10 variants. RESULTS The association of the TLR1/6/10 locus with anti-H pylori IgG titers (rs12233670; β = -0.267 ± SE 0.034; P = 4.42 × 10-15) presented with high heterogeneity and failed replication. Anti-H pylori IgG titers declined within 2-4 years after eradication treatment (P = 0.004), and decreased over time in patients with premalignant gastric lesions (P < 0.001). Variation at the TLR1/6/10 locus affected TLR1-mediated cytokine production and TLR1 surface expression on monocytes (P = 0.016) and neutrophils (P = 0.030), but not mRNA levels. CONCLUSIONS The association between anti-H pylori IgG titers and TLR1/6/10 locus was not replicated across cohorts, possibly owing to dependency of anti-H pylori IgG titers on therapy, clearance, and antibody decay. H pylori-mediated immune cell activation is partly mediated via TLR1 signaling, which in turn is affected by genetic variation.
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Affiliation(s)
- Suk Yee Lam
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Michiel C Mommersteeg
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Bingting Yu
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Linda Broer
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Manon C W Spaander
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Fabian Frost
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Stefan Weiss
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany; Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Henry Völzke
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Markus M Lerch
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Ben Schöttker
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany; Network Aging Research, Heidelberg University, Heidelberg, Germany
| | - Yan Zhang
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany
| | - Hannah Stocker
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany; Network Aging Research, Heidelberg University, Heidelberg, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany; Network Aging Research, Heidelberg University, Heidelberg, Germany
| | - Daniel Levy
- Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, Massachusetts, USA; Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA
| | - Shih-Jen Hwang
- Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, Massachusetts, USA; Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA
| | - Alexis C Wood
- USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas, USA
| | - Stephen S Rich
- Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA
| | - Jerome I Rotter
- Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA
| | - Kent D Taylor
- Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA
| | - Russell P Tracy
- Laboratory for Clinical Biochemistry Research, University of Vermont College of Medicine, Colchester, Vermont, USA
| | | | - Marcis Leja
- Institute of Clinical and Preventive Medicine, Faculty of Medicine, University of Latvia, Riga, Latvia
| | - Janis Klovins
- Latvian Biomedical Research and Study Center, Riga, Latvia
| | - Raitis Peculis
- Latvian Biomedical Research and Study Center, Riga, Latvia
| | - Dace Rudzite
- Institute of Clinical and Preventive Medicine, Faculty of Medicine, University of Latvia, Riga, Latvia
| | | | - Girts Skenders
- Institute of Clinical and Preventive Medicine, Faculty of Medicine, University of Latvia, Riga, Latvia
| | - Vita Rovite
- Latvian Biomedical Research and Study Center, Riga, Latvia
| | - André Uitterlinden
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Ernst J Kuipers
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Gwenny M Fuhler
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Georg Homuth
- Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands.
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Risk Prediction for Gastric Cancer Using GWAS-Identifie Polymorphisms, Helicobacter pylori Infection and Lifestyle-Related Risk Factors in a Japanese Population. Cancers (Basel) 2021; 13:cancers13215525. [PMID: 34771687 PMCID: PMC8583059 DOI: 10.3390/cancers13215525] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 10/27/2021] [Accepted: 10/30/2021] [Indexed: 11/18/2022] Open
Abstract
Simple Summary Gastric cancer remains the major cancer in Japan and worldwide. It is expected that practical intervention strategies for prevention, such as personalized approaches based on genetic risk models, will be developed. Here, we developed and validated a risk prediction model for gastric cancer using genetic, biological, and lifestyle-related risk factors. Results showed that the combination of selected GWAS-identified SNP polymorphisms and other predictors provided high discriminatory accuracy and good calibration in both the derivation and validation studies; however, the contribution of genetic factors to risk prediction was limited. The greatest contributor to risk prediction was ABCD classification (Helicobacter pylori infection-related factor). Abstract Background: As part of our efforts to develop practical intervention applications for cancer prevention, we investigated a risk prediction model for gastric cancer based on genetic, biological, and lifestyle-related risk factors. Methods: We conducted two independent age- and sex-matched case–control studies, the first for model derivation (696 cases and 1392 controls) and the second (795 and 795) for external validation. Using the derivation study data, we developed a prediction model by fitting a conditional logistic regression model using the predictors age, ABCD classification defined by H. pylori infection and gastric atrophy, smoking, alcohol consumption, fruit and vegetable intake, and 3 GWAS-identified polymorphisms. Performance was assessed with regard to discrimination (area under the curve (AUC)) and calibration (calibration plots and Hosmer–Lemeshow test). Results: A combination of selected GWAS-identified polymorphisms and the other predictors provided high discriminatory accuracy and good calibration in both the derivation and validation studies, with AUCs of 0.77 (95% confidence intervals: 0.75–0.79) and 0.78 (0.77–0.81), respectively. The calibration plots of both studies stayed close to the ideal calibration line. In the validation study, the environmental model (nongenetic model) was significantly more discriminative than the inclusive model, with an AUC value of 0.80 (0.77–0.82). Conclusion: The contribution of genetic factors to risk prediction was limited, and the ABCD classification (H. pylori infection-related factor) contributes most to risk prediction of gastric cancer.
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Lifestyles, genetics, and future perspectives on gastric cancer in east Asian populations. J Hum Genet 2021; 66:887-899. [PMID: 34267306 PMCID: PMC8384627 DOI: 10.1038/s10038-021-00960-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 06/08/2021] [Accepted: 07/05/2021] [Indexed: 12/17/2022]
Abstract
The prevalence of gastric cancer (GC) differs among regions worldwide, with the highest occurrence in east Asia. Thus, its etiology, with respect to ethnic background, environmental factors, and lifestyles, is also thought to differ essentially. In addition, etiology of GC is speculated to be changing due to the recent decrease in the Helicobacter pylori (H. pylori) infection in Japan. State-of-the-art somatic/germline cancer genomics has clarified the etiologies of gastric carcinogenesis. In this review article, we summarize past and present milestones in our understanding of GC achieved through genomic approaches, including a recent report that revealed higher-than-expected frequencies of GCs attributed to east Asian-specific germline variants in ALDH2 or CDH1 in combination with lifestyles. Based on this updated knowledge, we also discuss the possible impact of and high-risk approaches for GCs in the upcoming "H. pylori-negative era."
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Usui Y, Matsuo K, Oze I, Ugai T, Koyanagi Y, Maeda Y, Ito H, Hishida A, Takeuchi K, Tamura T, Tsukamoto M, Kadomatsu Y, Hara M, Nishida Y, Shimoshikiryo I, Takezaki T, Ozaki E, Matsui D, Watanabe I, Suzuki S, Watanabe M, Nakagawa-Senda H, Mikami H, Nakamura Y, Arisawa K, Uemura H, Kuriki K, Takashima N, Kadota A, Ikezaki H, Murata M, Nakatochi M, Momozawa Y, Kubo M, Wakai K. Impact of PSCA Polymorphisms on the Risk of Duodenal Ulcer. J Epidemiol 2021; 31:12-20. [PMID: 31839644 PMCID: PMC7738644 DOI: 10.2188/jea.je20190184] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 11/22/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND While duodenal ulcer (DU) and gastric cancer (GC) are both H. pylori infection-related diseases, individuals with DU are known to have lower risk for GC. Many epidemiological studies have identified the PSCA rs2294008 T-allele as a risk factor of GC, while others have found an association between the rs2294008 C-allele and risk of DU and gastric ulcer (GU). Following these initial reports, however, few studies have since validated these associations. Here, we aimed to validate the association between variations in PSCA and the risk of DU/GU and evaluate its interaction with environmental factors in a Japanese population. METHODS Six PSCA SNPs were genotyped in 584 DU cases, 925 GU cases, and 8,105 controls from the Japan Multi-Institutional Collaborative Cohort (J-MICC). Unconditional logistic regression models were applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between the SNPs and risk of DU/GU. RESULTS PSCA rs2294008 C-allele was associated with per allele OR of 1.34 (95% CI, 1.18-1.51; P = 2.28 × 10-6) for the risk of DU. This association was independent of age, sex, study site, smoking habit, drinking habit, and H. pylori status. On the other hand, we did not observe an association between the risk of GU and PSCA SNPs. CONCLUSIONS Our study confirms an association between the PSCA rs2294008 C-allele and the risk of DU in a Japanese population.
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Affiliation(s)
- Yoshiaki Usui
- Division of Cancer Information and Control, Department of Preventive Medicine, Aichi Cancer Center, Nagoya, Japan
- Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceuticals Sciences, Okayama, Japan
| | - Keitaro Matsuo
- Division of Cancer Epidemiology and Prevention, Department of Preventive Medicine, Aichi Cancer Center, Nagoya, Japan
- Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Isao Oze
- Division of Cancer Epidemiology and Prevention, Department of Preventive Medicine, Aichi Cancer Center, Nagoya, Japan
| | - Tomotaka Ugai
- Division of Cancer Epidemiology and Prevention, Department of Preventive Medicine, Aichi Cancer Center, Nagoya, Japan
| | - Yuriko Koyanagi
- Division of Cancer Information and Control, Department of Preventive Medicine, Aichi Cancer Center, Nagoya, Japan
| | - Yoshinobu Maeda
- Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceuticals Sciences, Okayama, Japan
| | - Hidemi Ito
- Division of Cancer Information and Control, Department of Preventive Medicine, Aichi Cancer Center, Nagoya, Japan
- Division of Descriptive Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Asahi Hishida
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kenji Takeuchi
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takashi Tamura
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mineko Tsukamoto
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yuka Kadomatsu
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Megumi Hara
- Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | - Yuichiro Nishida
- Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | - Ippei Shimoshikiryo
- Department of International Island and Community Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Toshiro Takezaki
- Department of International Island and Community Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Etsuko Ozaki
- Department of Epidemiology for Community Health and Medicine Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Daisuke Matsui
- Department of Epidemiology for Community Health and Medicine Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Isao Watanabe
- Department of Epidemiology for Community Health and Medicine Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Sadao Suzuki
- Department of Public Health, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Miki Watanabe
- Department of Public Health, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Hiroko Nakagawa-Senda
- Department of Public Health, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Haruo Mikami
- Cancer Prevention Center, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Yohko Nakamura
- Cancer Prevention Center, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Kokichi Arisawa
- Department of Preventive Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Hirokazu Uemura
- Department of Preventive Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Kiyonori Kuriki
- Laboratory of Public Health, University of Shizuoka, Shizuoka, Japan
| | - Naoyuki Takashima
- Department of Public Health, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Aya Kadota
- Department of Public Health, Shiga University of Medical Science, Otsu, Japan
| | - Hiroaki Ikezaki
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Masayuki Murata
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Masahiro Nakatochi
- Department of Nursing, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yukihide Momozawa
- Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Michiaki Kubo
- Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Kenji Wakai
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Qiu L, Qu X, He J, Cheng L, Zhang R, Sun M, Yang Y, Wang J, Wang M, Zhu X, Guo W. Predictive model for risk of gastric cancer using genetic variants from genome-wide association studies and high-evidence meta-analysis. Cancer Med 2020; 9:7310-7316. [PMID: 32777176 PMCID: PMC7541133 DOI: 10.1002/cam4.3354] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 07/15/2020] [Accepted: 07/16/2020] [Indexed: 02/05/2023] Open
Abstract
Genome-wide association studies (GWAS) have identified some single nucleotide polymorphisms (SNPs) associated with the risk of gastric cancer (GCa). However, currently, there is no published predictive model to assess the risk of GCa. In the present study, risk-associated SNPs derived from GWAS and large meta-analyses were selected to construct a predictive model to assess the risk of GCa. A total of 1115 GCa cases and 1172 controls from the eastern Chinese population were included. Logistic regression models were used to identify SNPs that correlated with the risk of GCa. A predictive model to assess the risk of GCa was established by receiver operating characteristic curve analysis. Multifactor dimensionality reduction (MDR) and classification and regression tree (CART) were applied to calculate the effect of high-order gene-environment interactions on risk of the cancer. A total of 42 SNPs were selected for further analysis. The results revealed that ASH1L rs80142782, PKLR rs3762272, PRKAA1 rs13361707, MUC1 rs4072037, PSCA rs2294008, and PLCE1 rs2274223 polymorphisms were associated with a risk of GCa. The area under curve considering both genetic factors and BMI was 3.10% higher than that of BMI alone. MDR analysis revealed that rs13361707 and rs4072307 variants and BMI had interaction effects on susceptibility to GCa, with the highest predictive accuracy (61.23%) and cross-validation consistency (100/100). CART analysis also supported this interaction model that non-overweight status and a six SNP panel could synergistically increase the susceptibility to GCa. The six SNP panel for predicting the risk of GCa may provide new tools for prevention of the cancer based on GWAS and large meta-analyses derived genetic variants.
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Affiliation(s)
- Lixin Qiu
- Department of Medical OncologyFudan University Shanghai Cancer CenterDepartment of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
- Cancer InstituteCollaborative Innovation Center for Cancer MedicineFudan University Shanghai Cancer CenterShanghaiChina
| | - Xiaofei Qu
- Cancer InstituteCollaborative Innovation Center for Cancer MedicineFudan University Shanghai Cancer CenterShanghaiChina
| | - Jing He
- Cancer InstituteCollaborative Innovation Center for Cancer MedicineFudan University Shanghai Cancer CenterShanghaiChina
| | - Lei Cheng
- Department of Medical OncologyFudan University Shanghai Cancer CenterDepartment of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
- Cancer InstituteCollaborative Innovation Center for Cancer MedicineFudan University Shanghai Cancer CenterShanghaiChina
| | - Ruoxin Zhang
- Cancer InstituteCollaborative Innovation Center for Cancer MedicineFudan University Shanghai Cancer CenterShanghaiChina
| | - Menghong Sun
- Department of PathologyFudan University Shanghai Cancer CenterShanghaiChina
| | - Yajun Yang
- Ministry of Education Key Laboratory of Contemporary Anthropology and State Key Laboratory of Genetic EngineeringSchool of Life SciencesFudan UniversityShanghaiChina
- Fudan‐Taizhou Institute of Health SciencesTaizhouChina
| | - Jiucun Wang
- Ministry of Education Key Laboratory of Contemporary Anthropology and State Key Laboratory of Genetic EngineeringSchool of Life SciencesFudan UniversityShanghaiChina
- Fudan‐Taizhou Institute of Health SciencesTaizhouChina
| | - Mengyun Wang
- Cancer InstituteCollaborative Innovation Center for Cancer MedicineFudan University Shanghai Cancer CenterShanghaiChina
| | - Xiaodong Zhu
- Department of Medical OncologyFudan University Shanghai Cancer CenterDepartment of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Weijian Guo
- Department of Medical OncologyFudan University Shanghai Cancer CenterDepartment of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
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Abstract
Background Intestinal and diffuse gastric adenocarcinomas differ in clinical, epidemiological and molecular features. However, most of the concepts related to the intestinal-type are translated to gastric adenocarcinoma in general; thus, the peculiarities of the diffuse-type are underappreciated. Results Besides its growing importance, there are many gaps about the diffuse-type carcinogenesis and, as a result, its epidemiologic and pathogenetic features remain poorly understood. Conclusions Alternative hypotheses to explain these features are discussed, including the role of the gastric microbiota, medical therapies, and modifications in the stomach’s microenvironment.
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Iwasaki RL, Ishiya K, Kanzawa-Kiriyama H, Kawai Y, Gojobori J, Satta Y. Evolutionary History of the Risk of SNPs for Diffuse-Type Gastric Cancer in the Japanese Population. Genes (Basel) 2020; 11:genes11070775. [PMID: 32664326 PMCID: PMC7396988 DOI: 10.3390/genes11070775] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 07/02/2020] [Accepted: 07/08/2020] [Indexed: 12/24/2022] Open
Abstract
A genome wide association study reported that the T allele of rs2294008 in a cancer-related gene, PSCA, is a risk allele for diffuse-type gastric cancer. This allele has the highest frequency (0.63) in Japanese in Tokyo (JPT) among 26 populations in the 1000 Genomes Project database. FST ≈ 0.26 at this single nucleotide polymorphism is one of the highest between JPT and the genetically close Han Chinese in Beijing (CHB). To understand the evolutionary history of the alleles in PSCA, we addressed: (i) whether the C non-risk allele at rs2294008 is under positive selection, and (ii) why the mainland Japanese population has a higher T allele frequency than other populations. We found that haplotypes harboring the C allele are composed of two subhaplotypes. We detected that positive selection on both subhaplotypes has occurred in the East Asian lineage. However, the selection on one of the subhaplotypes in JPT seems to have been relaxed or ceased after divergence from the continental population; this may have caused the elevation of T allele frequency. Based on simulations under the dual structure model (a specific demography for the Japanese) and phylogenetic analysis with ancient DNA, the T allele at rs2294008 might have had high frequency in the Jomon people (one of the ancestral populations of the modern Japanese); this may explain the high T allele frequency in the extant Japanese.
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Affiliation(s)
- Risa L. Iwasaki
- Department of Evolutionary Studies of Biosystems, SOKENDAI (The Graduate University for Advanced Studies), Kanagawa 240-0193, Japan; (R.L.I.); (J.G.)
| | - Koji Ishiya
- Bioproduction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Sapporo 062-8517, Japan;
| | | | - Yosuke Kawai
- Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo 162-8655, Japan;
| | - Jun Gojobori
- Department of Evolutionary Studies of Biosystems, SOKENDAI (The Graduate University for Advanced Studies), Kanagawa 240-0193, Japan; (R.L.I.); (J.G.)
| | - Yoko Satta
- Department of Evolutionary Studies of Biosystems, SOKENDAI (The Graduate University for Advanced Studies), Kanagawa 240-0193, Japan; (R.L.I.); (J.G.)
- Correspondence: ; Tel.: +81-46-858-1574
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10
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Guan F, Han W, Ni T, Zhao L, Zhang B, Li M, Luo X, Zhang L, Li X, Sun W, Zhang T. Risk of gastric ulcer contributed by genetic polymorphisms of PSCA: A case-control study based on Chinese Han population. Gene 2020; 757:144941. [PMID: 32640304 DOI: 10.1016/j.gene.2020.144941] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Revised: 05/29/2020] [Accepted: 07/01/2020] [Indexed: 02/07/2023]
Affiliation(s)
- Fanglin Guan
- College of Medicine and Forensics, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Wei Han
- College of Medicine and Forensics, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Tong Ni
- College of Medicine and Forensics, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Longrui Zhao
- College of Medicine and Forensics, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Bo Zhang
- School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Miao Li
- Department of Pathology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiaoqin Luo
- Department of Nutrition and Food Safety, School of Public Health, Xi'an Jiaotong University, Xi'an, China
| | - Lei Zhang
- Department of Laboratory Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiaoming Li
- Department of Emergency, Shaanxi People's Hospital, Xi'an, China
| | - Wei Sun
- Department of Digestion, Xi'an Central Hospital, Xi'an, China
| | - Tianxiao Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, China.
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11
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Cui H, Tang M, Zhang M, Liu S, Chen S, Zeng Z, Shen Z, Song B, Lu J, Jia H, Gu D, Zhang B. Variants in the PSCA gene associated with risk of cancer and nonneoplastic diseases: systematic research synopsis, meta-analysis and epidemiological evidence. Carcinogenesis 2019; 40:70-83. [PMID: 30407486 DOI: 10.1093/carcin/bgy151] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2018] [Revised: 10/01/2018] [Indexed: 12/19/2022] Open
Abstract
Variants in the prostate stem cell antigen (PSCA) gene have been linked with risk of multiple cancers and other diseases. But results have been inconclusive and no systematic research synopsis has been available. We did a comprehensive meta-analysis to investigate associations between variants in this gene and risk of nine cancers and four nonneoplastic diseases based on data from 55 publications including 81 961 cases and 442 932 controls. We graded levels of cumulative epidemiological evidence of a significant association using the Venice criteria and false-positive report probability tests. We performed functional annotation for these variants using data from the Encyclopedia of DNA Elements Project and other public databases. We found that six variants were nominally significantly associated with an increased or reduced risk of three cancers and three nonneoplastic diseases (P < 0.05). Cumulative evidence of an association was graded as strong for rs2294008 [odds ratio (OR) = 1.32, P = 5.1 × 10-33], rs2976392 (OR = 1.29, P = 1.8 × 10-8), rs9297976 (OR = 0.75, P = 1.4 × 10-7), rs2976391 (OR = 1.38, P = 6.1 × 10-5) and rs138377917 (OR = 0.53, P = 0.008) with gastric cancer, rs2294008 with bladder cancer (OR = 1.15, P = 8.0 × 10-19), gastritis (OR = 1.35, P = 1.2 × 10-5), duodenal ulcer (OR = 0.68, P = 2.4 × 10-57) and gastric ulcer (OR = 0.88, P = 1.7 × 10-7). Data from the Encyclopedia of DNA Elements Project and other databases showed that these variants and other variants correlated with them might fall in putative functional regions. In conclusion, this study provides summary evidence that variants in the PSCA gene are associated with risk of gastric and bladder cancer, gastritis, as well as duodenal and gastric ulcer and highlights the significant role of this gene in the pathogenesis of these diseases.
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Affiliation(s)
- Huijie Cui
- Department of Epidemiology and Biostatistics, Southwest School of Medicine and First Affiliated Hospital, Army Medical University, Chongqing, China
| | - Mingshuang Tang
- Department of Epidemiology and Biostatistics, Southwest School of Medicine and First Affiliated Hospital, Army Medical University, Chongqing, China
| | - Min Zhang
- Department of Epidemiology and Biostatistics, Southwest School of Medicine and First Affiliated Hospital, Army Medical University, Chongqing, China
| | - Shanshan Liu
- Department of Epidemiology and Biostatistics, Southwest School of Medicine and First Affiliated Hospital, Army Medical University, Chongqing, China
| | - Siyu Chen
- Department of Epidemiology and Biostatistics, Southwest School of Medicine and First Affiliated Hospital, Army Medical University, Chongqing, China
| | - Ziqian Zeng
- Department of Epidemiology and Biostatistics, Southwest School of Medicine and First Affiliated Hospital, Army Medical University, Chongqing, China
| | - Zhuozhi Shen
- Department of Epidemiology and Biostatistics, Southwest School of Medicine and First Affiliated Hospital, Army Medical University, Chongqing, China
| | - Bin Song
- Department of Epidemiology and Biostatistics, Southwest School of Medicine and First Affiliated Hospital, Army Medical University, Chongqing, China
| | - Jiachun Lu
- Department of Epidemiology, School of Public Health, Institute for Chemical Carcinogenesis, Guangzhou Medical University, Guangzhou, China
| | - Hong Jia
- Department of Epidemiology, School of Public Health, Southwest Medical University, Luzhou, China
| | - Dongqing Gu
- Department of Epidemiology and Biostatistics, Southwest School of Medicine and First Affiliated Hospital, Army Medical University, Chongqing, China
| | - Ben Zhang
- Department of Epidemiology and Biostatistics, Southwest School of Medicine and First Affiliated Hospital, Army Medical University, Chongqing, China.,Department of Epidemiology, School of Public Health, Institute for Chemical Carcinogenesis, Guangzhou Medical University, Guangzhou, China.,Department of Epidemiology, School of Public Health, Southwest Medical University, Luzhou, China.,Department of Epidemiology, School of Public Health, Shanghai Jiaotong University School of Medicine, Shanghai, China
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12
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Torruella-Loran I, Ramirez Viña MK, Zapata-Contreras D, Muñoz X, Garcia-Ramallo E, Bonet C, Gonzalez CA, Sala N, Espinosa-Parrilla Y. rs12416605:C>T in MIR938 associates with gastric cancer through affecting the regulation of the CXCL12 chemokine gene. Mol Genet Genomic Med 2019; 7:e832. [PMID: 31273931 PMCID: PMC6687864 DOI: 10.1002/mgg3.832] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 05/23/2019] [Accepted: 05/31/2019] [Indexed: 12/11/2022] Open
Abstract
Background MicroRNAs are small regulatory RNAs with important roles in carcinogenesis. Genetic variants in these regulatory molecules may contribute to disease. We aim to identify allelic variants in microRNAs as susceptibility factors to gastric cancer using association studies and functional approaches. Methods Twenty‐one single nucleotide variants potentially functional, because of their location in either the seed, mature or precursor region of 22 microRNAs, were selected for association studies. Genetic association with gastric cancer in 365 cases and 1,284 matched controls (European Prospective Investigation into Cancer and Nutrition Cohort) was analysed using logistic regression. MicroRNA overexpression, transcriptome analysis, and target gene validation experiments were performed for functional studies. Results rs3746444:T>C, in the seed of MIR499A and mature MIR499B, associated with the cardia adenocarcinoma location; rs12416605:C>T, in the seed of MIR938, associated with the diffuse subtype; and rs2114358:T>C, in the precursor MIR1206, associated with the noncardia phenotype. In all cases, the association was inverse, indicating a protective affect against gastric cancer of the three minor allelic variants. MIR499 rs3746444:T>C and MIR1206 rs2114358:T>C are reported to affect the expression of these miRNAs, but the effect of MIR938 rs12416605:C>T is unknown yet. Functional approaches showed that the expression of MIR938 is affected by rs12416605:C>T and revealed that MIR938 could regulate a subset of cancer‐related genes in an allele‐specific fashion. Furthermore, we demonstrated that CXCL12, a chemokine participating in gastric cancer metastasis, is specifically regulated by only one of the rs12416605:C>T alleles. Conclusion rs12416605 appears to be involved in gastric cancer by affecting the regulatory function of MIR938 on genes related to this cancer type, particularly on CXCL12 posttranscriptional regulation.
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Affiliation(s)
- Ignasi Torruella-Loran
- Department of Experimental and Health Sciences, IBE, Institute of Evolutionary Biology (Universitat Pompeu Fabra-CSIC), Barcelona, Spain
| | - María Karla Ramirez Viña
- School of Medicine, Universidad de Magallanes, Punta Arenas, Chile.,Laboratory of Molecular Medicine LMM, Center for Education, Healthcare and Investigation CADI, Universidad de Magallanes, Punta Arenas, Chile
| | - Daniela Zapata-Contreras
- School of Medicine, Universidad de Magallanes, Punta Arenas, Chile.,Laboratory of Molecular Medicine LMM, Center for Education, Healthcare and Investigation CADI, Universidad de Magallanes, Punta Arenas, Chile
| | - Xavier Muñoz
- Molecular Epidemiology Group, Translational Research Laboratory, Catalan Institute of Oncology-IDIBELL, Barcelona, Spain.,Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
| | - Eva Garcia-Ramallo
- Department of Experimental and Health Sciences, IBE, Institute of Evolutionary Biology (Universitat Pompeu Fabra-CSIC), Barcelona, Spain
| | - Catalina Bonet
- Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology-Bellvitge Biomedical Research Institute (ICO-IDIBELL), Barcelona, Spain
| | - Carlos A Gonzalez
- Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology-Bellvitge Biomedical Research Institute (ICO-IDIBELL), Barcelona, Spain
| | - Núria Sala
- Molecular Epidemiology Group, Translational Research Laboratory, Catalan Institute of Oncology-IDIBELL, Barcelona, Spain.,Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology-Bellvitge Biomedical Research Institute (ICO-IDIBELL), Barcelona, Spain
| | - Yolanda Espinosa-Parrilla
- Department of Experimental and Health Sciences, IBE, Institute of Evolutionary Biology (Universitat Pompeu Fabra-CSIC), Barcelona, Spain.,School of Medicine, Universidad de Magallanes, Punta Arenas, Chile.,Laboratory of Molecular Medicine LMM, Center for Education, Healthcare and Investigation CADI, Universidad de Magallanes, Punta Arenas, Chile
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13
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Heinrichs SKM, Hess T, Becker J, Hamann L, Vashist YK, Butterbach K, Schmidt T, Alakus H, Krasniuk I, Höblinger A, Lingohr P, Ludwig M, Hagel AF, Schildberg CW, Veits L, Gyvyte U, Weise K, Schüller V, Böhmer AC, Schröder J, Gehlen J, Kreuser N, Hofer S, Lang H, Lordick F, Malfertheiner P, Moehler M, Pech O, Vassos N, Rodermann E, Izbicki JR, Kruschewski M, Ott K, Schumann RR, Vieth M, Mangold E, Gasenko E, Kupcinskas L, Brenner H, Grimminger P, Bujanda L, Sopeña F, Espinel J, Thomson C, Pérez-Aísa Á, Campo R, Geijo F, Collette D, Bruns C, Messerle K, Gockel I, Nöthen MM, Lippert H, Ridwelski K, Lanas A, Keller G, Knapp M, Leja M, Kupcinskas J, García-González MA, Venerito M, Schumacher J. Evidence for PTGER4, PSCA, and MBOAT7 as risk genes for gastric cancer on the genome and transcriptome level. Cancer Med 2018; 7:5057-5065. [PMID: 30191681 PMCID: PMC6198243 DOI: 10.1002/cam4.1719] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Revised: 07/12/2018] [Accepted: 07/13/2018] [Indexed: 12/18/2022] Open
Abstract
Genetic associations between variants on chromosome 5p13 and 8q24 and gastric cancer (GC) have been previously reported in the Asian population. We aimed to replicate these findings and to characterize the associations at the genome and transcriptome level. We performed a fine‐mapping association study in 1926 GC patients and 2012 controls of European descent using high dense SNP marker sets on both chromosomal regions. Next, we performed expression quantitative trait locus (eQTL) analyses using gastric transcriptome data from 143 individuals focusing on the GC associated variants. On chromosome 5p13 the strongest association was observed at rs6872282 (P = 2.53 × 10−04) and on chromosome 8q24 at rs2585176 (P = 1.09 × 10−09). On chromosome 5p13 we found cis‐eQTL effects with an upregulation of PTGER4 expression in GC risk allele carrier (P = 9.27 × 10−11). On chromosome 8q24 we observed cis‐eQTL effects with an upregulation of PSCA expression in GC risk allele carrier (P = 2.17 × 10−47). In addition, we found trans‐eQTL effects for the same variants on 8q24 with a downregulation of MBOAT7 expression in GC risk allele carrier (P = 3.11 × 10−09). In summary, we confirmed and refined the previously reported GC associations at both chromosomal regions. Our data point to shared etiological factors between Asians and Europeans. Furthermore, our data imply an upregulated expression of PTGER4 and PSCA as well as a downregulated expression of MBOAT7 in gastric tissue as risk‐conferring GC pathomechanisms.
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Affiliation(s)
- Sophie K M Heinrichs
- Institute of Human Genetics, University of Bonn, Bonn, Germany.,Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
| | - Timo Hess
- Institute of Human Genetics, University of Bonn, Bonn, Germany.,Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
| | - Jessica Becker
- Institute of Human Genetics, University of Bonn, Bonn, Germany.,Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
| | - Lutz Hamann
- Institute for Microbiology and Hygiene, Charité University Medical Center Berlin, Berlin, Germany
| | - Yogesh K Vashist
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Katja Butterbach
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Thomas Schmidt
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Hakan Alakus
- Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany
| | - Iurii Krasniuk
- Department of General and Visceral Surgery, Municipal Hospital Solingen, Solingen, Germany
| | - Aksana Höblinger
- Department of Internal Medicine I, Community Hospital Mittelrhein, Koblenz, Germany
| | - Philipp Lingohr
- Department of General, Visceral, Thoracic and Vascular Surgery, University of Bonn, Bonn, Germany
| | - Monika Ludwig
- Association for Oncological Studies (Gefos), Dortmund, Germany
| | - Alexander F Hagel
- Department of Medicine I, Gastroenterology and Interventional Endoscopy, University of Erlangen, Erlangen, Germany
| | | | - Lothar Veits
- Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany
| | - Ugne Gyvyte
- Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Katharina Weise
- Institute of Human Genetics, University of Bonn, Bonn, Germany.,Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
| | - Vitalia Schüller
- Institute of Human Genetics, University of Bonn, Bonn, Germany.,Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.,Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany
| | - Anne C Böhmer
- Institute of Human Genetics, University of Bonn, Bonn, Germany.,Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
| | - Julia Schröder
- Institute of Human Genetics, University of Bonn, Bonn, Germany.,Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
| | - Jan Gehlen
- Institute of Human Genetics, University of Bonn, Bonn, Germany.,Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
| | - Nicole Kreuser
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Sebastian Hofer
- Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany
| | - Hauke Lang
- Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany
| | - Florian Lordick
- University Cancer Center Leipzig (UCCL), University Hospital of Leipzig, Leipzig, Germany
| | - Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
| | - Markus Moehler
- First Medical Clinic and Policlinic, University Medical Center, University of Mainz, Mainz, Germany
| | - Oliver Pech
- Department of Gastroenterology and Interventional Endoscopy, St. John of God Hospital, Regensburg, Germany
| | - Nikolaos Vassos
- Department of Surgery, University of Erlangen, Erlangen, Germany
| | - Ernst Rodermann
- Association of Medical Practices in Hematology and Internal Oncology, Troisdorf, Germany
| | - Jakob R Izbicki
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Martin Kruschewski
- Department of General and Visceral Surgery, Hospital Frankfurt Oder, Frankfurt Oder, Germany
| | - Katja Ott
- Department of General, Visceral and Thorax Surgery, RoMed Hospital Rosenheim, Rosenheim, Germany
| | - Ralf R Schumann
- Institute for Microbiology and Hygiene, Charité University Medical Center Berlin, Berlin, Germany
| | - Michael Vieth
- Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany
| | - Elisabeth Mangold
- Institute of Human Genetics, University of Bonn, Bonn, Germany.,Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
| | - Evita Gasenko
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga, Latvia.,Riga East University Hospital, Riga, Latvia
| | - Limas Kupcinskas
- Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.,German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Peter Grimminger
- Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany
| | - Luis Bujanda
- CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.,Department of Gastroenterology, Hospital Donostia/Instituto Biodonostia, Universidad del País Vasco (UPV/EHU), San Sebastián, Spain
| | - Federico Sopeña
- CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.,Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain.,Department of Gastroenterology, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
| | - Jesús Espinel
- Department of Gastroenterology, Complejo Hospitalario, León, Spain
| | - Concha Thomson
- Department of Gastroenterology, Hospital Obispo Polanco, Teruel, Spain
| | | | - Rafael Campo
- Department of Gastroenterology, Hospital Parc Tauli, Sabadell, Spain
| | - Fernando Geijo
- Department of Gastroenterology, Hospital Clínico Universitario, Salamanca, Spain
| | - Daniela Collette
- Association of Medical Practices in Hematology and Oncology, Dortmund, Germany
| | - Christiane Bruns
- Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany
| | - Katharina Messerle
- Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany
| | - Ines Gockel
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Markus M Nöthen
- Institute of Human Genetics, University of Bonn, Bonn, Germany.,Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
| | - Hans Lippert
- An-Institute for Quality Control in Surgery, Otto-von-Guericke University Hospital, Magdeburg, Germany
| | - Karsten Ridwelski
- An-Institute for Quality Control in Surgery, Otto-von-Guericke University Hospital, Magdeburg, Germany.,Department of Surgery, Hospital Magdeburg, Magdeburg, Germany
| | - Angel Lanas
- CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.,Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain.,Department of Gastroenterology, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
| | - Gisela Keller
- Institute of Pathology, Technical University of Munich, Munich, Germany
| | - Michael Knapp
- Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany
| | - Marcis Leja
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga, Latvia.,Riga East University Hospital, Riga, Latvia
| | - Juozas Kupcinskas
- Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Maria A García-González
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain.,Department of Gastroenterology, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain.,Instituto Aragonés de Ciencias de la Salud (IACS), Zaragoza, Spain
| | - Marino Venerito
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
| | - Johannes Schumacher
- Institute of Human Genetics, University of Bonn, Bonn, Germany.,Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.,Center of Human Genetics, University Hospital Marburg, Marburg, Germany
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14
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Association between PSCA gene polymorphisms and the risk of cancer: an updated meta-analysis and trial sequential analysis. Oncotarget 2017; 8:51766-51778. [PMID: 28881685 PMCID: PMC5584286 DOI: 10.18632/oncotarget.17011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Accepted: 03/30/2017] [Indexed: 01/25/2023] Open
Abstract
Previous studies have investigated the relationships between PSCA rs2294008 C>T and rs2976392 G>A polymorphisms and cancer susceptibility. However, the available findings remained inconsistent and even controversial. Thus, the aim of this meta-analysis was performed to clarify such associations. The online databases PubMed, EMBASE and Web of Science searched for relevant studies, covering all the papers published until September 1st, 2016. Data were pooled by odds ratios (ORs) with 95% confidence intervals (CIs) to evaluate the strength of such associations. Then, trial sequential analysis was performed to estimate whether the evidence of the results was firm. Overall, a significant increased risk of cancer was associated with PSCA rs2294008 C>T and rs2976392 G>A polymorphisms. For the PSCA rs2294008 polymorphism, when stratified by type of cancer, the results were significant especially in gastric cancer and bladder cancer. Moreover, in the subgroup analysis by ethnicity, significant results were detected in both Asian and Caucasian populations. Similarly, for the PSCA rs2976392 polymorphism, the stratification analyses by type of cancer showed that the results were significant only in gastric cancer. In addition, the stratification analyses by ethnicity detected that this polymorphism increased cancer risk only in Asian populations. Then, trial sequential analyses demonstrated that the results of the meta-analysis were based on sufficient evidence. Therefore, this meta-analysis suggested that the PSCA rs2294008 C>T and rs2976392 G>A polymorphisms might be associated with cancer susceptibility, which might act as a potential predicted biomarker for genetic susceptibility to cancer, especially in gastric cancer and bladd er cancer.
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15
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Cai M, Dai S, Chen W, Xia C, Lu L, Dai S, Qi J, Wang M, Wang M, Zhou L, Lei F, Zuo T, Zeng H, Zhao X. Environmental factors, seven GWAS-identified susceptibility loci, and risk of gastric cancer and its precursors in a Chinese population. Cancer Med 2017; 6:708-720. [PMID: 28220687 PMCID: PMC5345626 DOI: 10.1002/cam4.1038] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Revised: 01/16/2017] [Accepted: 01/18/2017] [Indexed: 12/15/2022] Open
Abstract
Gene–environment interactions may increase gastric cancer (GC) risk. Seven susceptibility loci identified by genome‐wide association studies (GWASs) suggest that genetic factors play a role in gastric carcinogenesis. Meanwhile, Helicobacter pylori (H. pylori) infection, smoking, and alcohol drinking are also important environmental factors for gastric cancer. However, studies to explore the role of gene–environment interactions in gastric carcinogenesis, and particularly the relationship between the seven susceptibility loci and their potential interactions with H. pylori infection, smoking, and alcohol drinking in risk of GC, and severe intestinal metaplasia (IM)/dysplasia, have been inconclusive. A total of 1273 subjects in a Chinese population were recruited, and genotyping was carried out using the competitive allele‐specific PCR (KASP) method. Unconditional logistic regression was applied to model the associations between genetic polymorphisms and the disease risk. Effect modifications by H. pylori infection, smoking and alcohol drinking were evaluated. PSCA rs2294008/rs2976392 showed a significant, multiplicative interaction with H. pylori infection in risk of GC. Meanwhile, PRKAA1 rs13361707 had an additive interaction with H. pylori infection. SLC52A3 rs13042395 showed an interaction with alcohol drinking in risk of GC. Moreover, three SNPs, MUC1 rs4072037, ZBTB20 rs9841504 and PRKAA1 rs13361707, were associated with precancerous gastric lesions (severe IM/dysplasia). Our data suggest that genetic predisposition factors identified by GWAS may interact with environmental risk factors, Particularly for H. pylori infection and alcohol consumption, to increase the risk of GC.
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Affiliation(s)
- Meng Cai
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shuyang Dai
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wanqing Chen
- National Office for Cancer Prevention and Control, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Changfa Xia
- National Office for Cancer Prevention and Control, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lingeng Lu
- Department of Chronic Disease Epidemiology, Yale School of Public Health, School of Medicine, Yale Cancer Center, Yale University, New Haven, Connecticut, USA
| | - Shuguang Dai
- Center for Disease Control and Prevention of Sheyang County, Sheyang, Jiangsu, China
| | - Jun Qi
- Department of Clinical Laboratory, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Minjie Wang
- Department of Clinical Laboratory, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Meilin Wang
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.,Department of Genetic Toxicology, the Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lanping Zhou
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fuhua Lei
- Department of Pathology, Feicheng People Hospital, Feicheng, Shandong, China
| | - Tingting Zuo
- National Office for Cancer Prevention and Control, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hongmei Zeng
- National Office for Cancer Prevention and Control, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaohang Zhao
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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16
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Turdikulova S, Dalimova D, Abdurakhimov A, Adilov B, Navruzov S, Yusupbekov A, Djuraev M, Abdujapparov S, Egamberdiev D, Mukhamedov R. Association of rs2294008 and rs9297976 Polymorphisms in PSCA Gene with Gastric Cancer Susceptibility in Uzbekistan. Cent Asian J Glob Health 2016; 5:227. [PMID: 29138729 PMCID: PMC5661186 DOI: 10.5195/cajgh.2016.227] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Introduction: Genetic factors play an important role in the development of gastric cancer (GC), a prevalent malignancy in Central Asia. Recent studies have shown that single-nucleotide polymorphisms (SNPs) in several genes are associated with increased GC risk, indicating that genetic variation contributes to gastric carcinogenesis. Located on chromosome 8q24.2, the prostate stem cell antigen (PSCA) gene encodes a 123-amino acid glycoprotein related to the cell-proliferation inhibition and cell-death induction activity. SNPs in PSCA gene have been found to be associated with gastric cancer risk in a genome-wide association study, but results were not conclusive. This study aimed to investigate the association between two polymorphic variants of PSCA gene (rs2294008 and rs9297976) and the susceptibility to gastric cancer in Uzbekistan. Methods: Two hundred sixty eight patients with gastric cancer and a control group of 248 healthy individuals were included in this study. DNA samples isolated from these groups were genotyped using PCR-RFLP method. Comparative analysis of resulting genotypes showed a statistically significant association between CT genotype and gastric cancer (p=0.03, additive model of inheritance, Cochran-Armitage trend test). Results: Comparative analysis of the distribution of genotypes of rs2976392 polymorphism did not show a statistically significant difference; however, analysis of the distribution of the rs2976392 genotypes in a subgroup of young women revealed a statistically significant (p = 0.04, additive model of inheritance, Cochran-Armitage trend test) increase in the incidence of AA (38%) and AG (56%) genotypes in patients with GC, compared to the controls (20% and 40%). Conclusion: Our findings support that PSCA rs2294008 and rs9297976 polymorphism may contribute to the susceptibility to gastric cancer. Genotyping of these polymorphisms can potentially be recommended as one of the criteria for identification of high risk groups for gastric cancer development in Uzbekistan.
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Affiliation(s)
- Shahlo Turdikulova
- Institute of Bioorganic Chemistry Academy of Sciences Republic of Uzbekistan
| | - Dilbar Dalimova
- Institute of Bioorganic Chemistry Academy of Sciences Republic of Uzbekistan
| | - Abror Abdurakhimov
- Institute of Bioorganic Chemistry Academy of Sciences Republic of Uzbekistan
| | - Bekzod Adilov
- Institute of Bioorganic Chemistry Academy of Sciences Republic of Uzbekistan
| | - Sarimbek Navruzov
- National Cancer Center of the Ministry of Health of the Republic of Uzbekistan
| | - Abror Yusupbekov
- National Cancer Center of the Ministry of Health of the Republic of Uzbekistan
| | - Mirjalol Djuraev
- National Cancer Center of the Ministry of Health of the Republic of Uzbekistan
| | | | - Dilshod Egamberdiev
- National Cancer Center of the Ministry of Health of the Republic of Uzbekistan
| | - Rustam Mukhamedov
- Institute of Bioorganic Chemistry Academy of Sciences Republic of Uzbekistan
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17
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Hugen S, Thomas RE, German AJ, Burgener IA, Mandigers PJJ. Gastric carcinoma in canines and humans, a review. Vet Comp Oncol 2016; 15:692-705. [PMID: 27549077 DOI: 10.1111/vco.12249] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Revised: 05/06/2016] [Accepted: 05/20/2016] [Indexed: 02/06/2023]
Abstract
Gastric carcinoma (GC) is the most common neoplasm in the stomach of dogs. Although incidence in the general population is reported to be low, breed-specific GC has a high incidence. Median age at presentation ranges from 8 to approximately 10 years. The disease is mostly located in the lesser curvature and antropyloric region of the stomach. Unfortunately, diagnosis is usually made when the disease is at an advanced stage and, therefore, prognosis is poor. Due to similarities in clinical presentation, diagnosis, histology and prognosis, canine GC may serve as a valuable model for human GC. Extensive pedigrees of canine gastric carcinoma cases could reveal insights for human gastric carcinoma. Putative species differences include the role of Helicobacter in pathogenesis, the wide array of genetic data and screening available for humans, and treatment protocols that are available for human GC.
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Affiliation(s)
- S Hugen
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - R E Thomas
- Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - A J German
- School of Veterinary Science, University of Liverpool, Neston, UK
| | - I A Burgener
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - P J J Mandigers
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
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18
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Sobota RS, Kodaman N, Mera R, Piazuelo MB, Bravo LE, Pazos A, Zabaleta J, Delgado AG, El-Rifai W, Morgan DR, Wilson KT, Correa P, Williams SM, Schneider BG. Epigenetic and genetic variation in GATA5 is associated with gastric disease risk. Hum Genet 2016; 135:895-906. [PMID: 27225266 PMCID: PMC4947561 DOI: 10.1007/s00439-016-1687-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 05/17/2016] [Indexed: 12/12/2022]
Abstract
Gastric cancer incidence varies considerably among populations, even those with comparable rates of Helicobacter pylori infection. To test the hypothesis that genetic variation plays a role in gastric disease, we assessed the relationship between genotypes and gastric histopathology in a Colombian study population, using a genotyping array of immune-related single nucleotide polymorphisms (SNPs). Two synonymous SNPs (rs6061243 and rs6587239) were associated with progression of premalignant gastric lesions in a dominant-effects model after correction for multiple comparisons (p = 2.63E-07 and p = 7.97E-07, respectively); effect sizes were β = -0.863 and β = -0.815, respectively, where β is an estimate of effect on histopathology scores, which ranged from 1 (normal) to 5 (dysplasia). In our replication cohort, a second Colombian population, both SNPs were associated with histopathology when additively modeled (β = -0.256, 95 % CI = -0.47, -0.039; and β = -0.239, 95 % CI = -0.45, -0.024), and rs6587239 was significantly associated in a dominant-effects model (β = -0.330, 95 % CI = -0.66, 0.00). Because promoter methylation of GATA5 has previously been associated with gastric cancer, we also tested for the association of methylation status with more advanced histopathology scores in our samples and found a significant relationship (p = 0.001). A multivariate regression model revealed that the effects of both the promoter methylation and the exonic SNPs in GATA5 were independent. A SNP-by-methylation interaction term was also significant. This interaction between GATA5 variants and GATA5 promoter methylation indicates that the association of either factor with gastric disease progression is modified by the other.
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Affiliation(s)
- Rafal S Sobota
- Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Nuri Kodaman
- Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, OH, USA
- Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Robertino Mera
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, 2215 Garland Avenue, Nashville, TN 37232, USA
| | - M Blanca Piazuelo
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, 2215 Garland Avenue, Nashville, TN 37232, USA
| | - Luis E Bravo
- Department of Pathology, School of Medicine, Universidad del Valle, Cali 760043, Colombia
| | - Alvaro Pazos
- Department of Biology, University of Nariño, Pasto 520002, Colombia
| | - Jovanny Zabaleta
- Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Alberto G Delgado
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, 2215 Garland Avenue, Nashville, TN 37232, USA
| | - Wael El-Rifai
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Veterans Affairs, Veterans Affairs Tennessee Valley Healthcare System and Office of Medical Research, Nashville, TN, USA
| | - Douglas R Morgan
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, 2215 Garland Avenue, Nashville, TN 37232, USA
| | - Keith T Wilson
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, 2215 Garland Avenue, Nashville, TN 37232, USA
- Department of Veterans Affairs, Veterans Affairs Tennessee Valley Healthcare System and Office of Medical Research, Nashville, TN, USA
| | - Pelayo Correa
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, 2215 Garland Avenue, Nashville, TN 37232, USA
| | - Scott M Williams
- Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, OH, USA
- Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Barbara G Schneider
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, 2215 Garland Avenue, Nashville, TN 37232, USA
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19
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PSCA rs2294008 polymorphism contributes to the decreased risk for cervical cancer in a Chinese population. Sci Rep 2016; 6:23465. [PMID: 27001215 PMCID: PMC4802316 DOI: 10.1038/srep23465] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Accepted: 03/08/2016] [Indexed: 12/24/2022] Open
Abstract
Recently, three genome-wide association studies have identified the PSCA (prostate stem cell antigen) rs2294008 polymorphism (C > T) associated with susceptibility to gastric cancer, bladder cancer, and duodenal ulcers, highlighting its critical role in disease pathogenesis. Given PSCA is reported to be overexpressed in cervical cancer and the rs2294008 can influence PSCA transcription, we aimed to determine the role of rs2294008 in susceptibility to cervical cancer. The genotyping was performed in the 1126 cases and 1237 controls. Our results showed the rs2294008 TT genotype significantly associated with a reduced risk of cervical cancer (adjusted OR = 0.55, 95% CI = 0.38-0.79; recessive model). Stratified analyses revealed that the association was restricted to the subgroups of age > 49 years, parity ≤ 1, abortion and early-stage cervical cancer. Immunohistochemistry assay showed the individuals carrying the TT genotype having lower PSCA expression than those with CC/CT genotypes. In summary, the PSCA rs2294008 polymorphism may serve as a biomarker of cervical cancer, particularly of early-stage cervical cancer.
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20
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Qiu LX, Cheng L, He J, Zhou ZR, Wang MY, Zhou F, Guo WJ, Li J, Sun MH, Zhou XY, Wang YN, Yang YJ, Wang JC, Jin L, Zhu XD, Wei QY. PSCA polymorphisms and gastric cancer susceptibility in an eastern Chinese population. Oncotarget 2016; 7:9420-8. [PMID: 26848528 PMCID: PMC4891049 DOI: 10.18632/oncotarget.7137] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Accepted: 01/19/2016] [Indexed: 02/07/2023] Open
Abstract
The prostate stem cell antigen (PSCA) gene, which encodes a prostate-specific antigen (PSA), was identified as a gene involved in cell adhesion and proliferation. The associations between the PSCA rs2294008 and rs2976392 single nucleotide polymorphisms (SNPs) and gastric cancer (GCa) susceptibility were still controversial. To derive a more precise estimation of the associations, we conducted a case-control study of 1,124 cases and 1,192 controls in an eastern Chinese population. We found that the rs2294008T variant genotypes were associated with an increased GCa risk in this study population (CT vs CC, OR=1.59, 95% CI=1.33-1.89 and CT+TT vs CC, OR=1.38, 95% CI=1.17-1.62). For SNP rs2976392, the variant A genotypes were also associated with an increased GCa risk (AG vs GG, OR=1.61, 95% CI=1.35-1.91 and AG+AA vs GG, OR=1.47, 95% CI=1.25-1.74). The results were further validated by a meta-analysis. In conclusion, the results indicated that the PSCA rs2294008 T and rs2976392 A alleles were low-penetrate risk factors for GCa in this study population. However, large and well-designed studies are warranted to validate our findings.
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Affiliation(s)
- Li-Xin Qiu
- 1 Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- 2 Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Lei Cheng
- 2 Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Jing He
- 3 Department of Pediatric Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Zhi-Rui Zhou
- 4 Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Meng-Yun Wang
- 2 Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Fei Zhou
- 2 Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Wei-Jian Guo
- 1 Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jin Li
- 1 Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Meng-Hong Sun
- 5 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Xiao-Yan Zhou
- 5 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Ya-Nong Wang
- 6 Department of Gastric Cancer & Soft Tissue Sarcoma Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Ya-Jun Yang
- 7 Ministry of Education Key Laboratory of Contemporary Anthropology and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
- 8 Fudan-Taizhou Institute of Health Sciences, Taizhou, China
| | - Jiu-Cun Wang
- 7 Ministry of Education Key Laboratory of Contemporary Anthropology and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
- 8 Fudan-Taizhou Institute of Health Sciences, Taizhou, China
| | - Li Jin
- 7 Ministry of Education Key Laboratory of Contemporary Anthropology and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
- 8 Fudan-Taizhou Institute of Health Sciences, Taizhou, China
| | - Xiao-Dong Zhu
- 1 Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Qing-Yi Wei
- 2 Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
- 9 Duke Cancer Institute, Duke University Medical Center, and Department of Medicine, Duke University School of Medicine, Durham, NC, USA
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Chandra V, Kim JJ, Gupta U, Mittal B, Rai R. Impact of DCC (rs714) and PSCA (rs2294008 and rs2976392) Gene Polymorphism in Modulating Cancer Risk in Asian Population. Genes (Basel) 2016; 7:genes7020009. [PMID: 26891331 PMCID: PMC4773753 DOI: 10.3390/genes7020009] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Revised: 02/01/2016] [Accepted: 02/04/2016] [Indexed: 12/12/2022] Open
Abstract
Multiple studies have investigated the association of gene variant of Deleted in colorectal carcinoma (DCC) and Prostate Stem cell antigen (PSCA) with various cancer susceptibility; however, the results are discrepant. Since SNPs are emerging as promising biomarker of cancer susceptibility, here, we aimed to execute a meta-analysis of DCC (rs714 A > G) and PSCA (rs2294008 C > T, rs2976392 G > A) polymorphism to demonstrate the more accurate strength of these associations. We followed a rigorous inclusion/exclusion criteria and calculated the pooled odds ratios (ORs) and 95% confidence intervals (CIs). Overall, the pooled analysis showed that the DCC rs714 conferred increased risk of cancer only in Asians (AA vs. GG: OR = 1.86, p ≤ 0.0001; AG vs. GG: OR = 1.43, p = 0.005; GA + AA vs. GG: OR = 1.66, p ≤ 0.0001; AA vs. GG + GA; OR = 1.52, p ≤ 0.004, A vs. G allele: OR = 1.41, p ≤ 0.0001). PSCA rs2294008 was associated with increased overall cancer risk (TT vs. CC: OR = 1.28, p = 0.002; CT vs. CC: OR = 1.21, p ≤ 0.0001; CT + TT vs. CC: OR = 1.24, p ≤ 0.0001; TT vs. CC + CT; OR = 1.17, p ≤ 0.005, T vs. C allele: OR = 1.16, p ≤ 0.0001); however, in stratified analysis this association was limited only to gastric and bladder cancer and the strength was more prominent in Asians. In contrast, the PSCA rs2976392 SNP did not modulate the cancer risk. Therefore, we concluded that rs714 and rs2294008 polymorphism may represent a potential genetic biomarker for cancer risk in Asians and gastric as well as bladder cancer, respectively. However, since our study is limited to Asians and cancer types, further larger studies involving other cancers and/or population, gene-environment interactions and the mechanism of DCC and PSCA gene deregulation are desired to define the role of genotype with overall cancer risk.
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Affiliation(s)
- Vishal Chandra
- Department of Biosciences, Integral University, Lucknow 226026 (Uttar Pradesh), India.
| | - Jong Joo Kim
- School of Biotechnology, Yeungnam University, Gyeongsan, Gyeongbuk 712-749, Korea.
| | - Usha Gupta
- Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), Lucknow 226014 (Uttar Pradesh), India.
| | - Balraj Mittal
- Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), Lucknow 226014 (Uttar Pradesh), India.
| | - Rajani Rai
- School of Biotechnology, Yeungnam University, Gyeongsan, Gyeongbuk 712-749, Korea.
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Ahn HJ, Lee DS. Helicobacter pylori in gastric carcinogenesis. World J Gastrointest Oncol 2015; 7:455-65. [PMID: 26690981 PMCID: PMC4678392 DOI: 10.4251/wjgo.v7.i12.455] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2015] [Revised: 10/10/2015] [Accepted: 11/03/2015] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer still is a major concern as the third most common cancer worldwide, despite declining rates of incidence in many Western countries. Helicobacter pylori (H. pylori) is the major cause of gastric carcinogenesis, and its infection insults gastric mucosa leading to the occurrence of atrophic gastritis which progress to intestinal metaplasia, dysplasia, early gastric cancer, and advanced gastric cancer consequently. This review focuses on multiple factors including microbial virulence factors, host genetic factors, and environmental factors, which can heighten the chance of occurrence of gastric adenocarcinoma due to H. pylori infection. Bacterial virulence factors are key components in controlling the immune response associated with the induction of carcinogenesis, and cagA and vacA are the most well-known pathogenic factors. Host genetic polymorphisms contribute to regulating the inflammatory response to H. pylori and will become increasingly important with advancing techniques. Environmental factors such as high salt and smoking may also play a role in gastric carcinogenesis. It is important to understand the virulence factors, host genetic factors, and environmental factors interacting in the multistep process of gastric carcinogenesis. To conclude, prevention via H. pylori eradication and controlling environmental factors such as diet, smoking, and alcohol is an important strategy to avoid H. pylori-associated gastric carcinogenesis.
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23
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Wen R, Gao F, Zhou CJ, Jia YB. Polymorphisms in mucin genes in the development of gastric cancer. World J Gastrointest Oncol 2015; 7:328-337. [PMID: 26600932 PMCID: PMC4644855 DOI: 10.4251/wjgo.v7.i11.328] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2015] [Revised: 07/01/2015] [Accepted: 09/07/2015] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer (GC) is the third leading cause of cancer-related death worldwide. In areas of high prevalence, such as Japan, South Korea and China, most cases of GC are related to Helicobacter pylori (H. pylori), which involves well-characterized sequential stages, including infection, atrophic gastritis, intestinal metaplasia, dysplasia, and GC. Mucins are the most abundant high-molecular-weight glycoproteins in mucus, which is the first line of defense and plays a major role in blocking pathogenic factors. Normal gastric mucosa shows expression of MUC1, MUC5AC and MUC6 that is specific to cell type. However, the specific pattern of MUC1, MUC5AC and MUC6 expression is changed in gastric carcinogenesis, accompanied by de novo expression of secreted MUC2. Recent studies have provided evidence that variations in these mucin genes affect many steps of GC development, such as H. pylori infection, and gastric precancerous lesions. In this review, we focus on studies of the association between polymorphisms in mucin genes and development of GC. This information should be helpful for the early detection, surveillance, and treatment of GC.
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Geng P, Li J, Wang N, Ou J, Xie G, Liu C, Zhao X, Xiang L, Liao Y, Liang H. PSCA rs2294008 Polymorphism with Increased Risk of Cancer. PLoS One 2015; 10:e0136269. [PMID: 26308216 PMCID: PMC4550426 DOI: 10.1371/journal.pone.0136269] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2014] [Accepted: 08/03/2015] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Published data on the association between PSCA rs2294008 polymorphism and cancer risk have implicated inconclusive results. To determine the relationship and to precisely assess the effect size estimate of the association, we performed a meta-analysis. METHODS We searched published literature in Embase and PubMed databases using the search terms "PSCA", "prostate stem cell antigen", "variants", "polymorphism", "polymorphisms", and "cancer". A total of 21 eligible articles were retrieved, with 27, 197 cancer cases and 48, 237 controls. RESULTS On the whole, we found the association between PSCA rs2294008 polymorphism and cancer risk was statistically significant: TT vs CC: OR = 1.18, 95% CI, 1.10 to 1.27; TT + CT vs CC: OR = 1.08, 95% CI, 1.05 to 1.10; TT vs CT + CC: OR = 1.14, 95% CI, 1.07 to 1.21; T vs C: OR = 1.10, 95% CI, 1.06 to 1.14; CT vs CC: OR = 1.10, 95% CI, 1.06 to 1.13. Stratified analyses in cancer type and ethnicity showed similar results. CONCLUSIONS Based on the statistical evidence, we can draw a conclusion that the rs2294008 polymorphism of PSCA gene is likely to play a role in cancer carcinogenesis, especially in gastric cancer and bladder cancer.
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Affiliation(s)
- Peiliang Geng
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China
| | - Jianjun Li
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China
| | - Ning Wang
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China
| | - Juanjuan Ou
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China
| | - Ganfeng Xie
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China
| | - Chen Liu
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China
| | - Xiaoxin Zhao
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China
| | - Lisha Xiang
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China
| | - Yunmei Liao
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China
| | - Houjie Liang
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China
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Gu Y, Dai QS, Hua RX, Zhang B, Zhu JH, Huang JW, Xie BH, Xiong SQ, Tan GS, Li HP. PSCA s2294008 C>T and rs2976392 G>A polymorphisms contribute to cancer susceptibility: evidence from published studies. Genes Cancer 2015; 6:254-264. [PMID: 26124924 PMCID: PMC4482246 DOI: 10.18632/genesandcancer.63] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2015] [Accepted: 04/27/2015] [Indexed: 12/17/2022] Open
Abstract
PSCA gene plays an important role in cell adhesion, proliferation and survival. Increasing studies have focused on the association of PSCA gene rs2294008 C>T and rs2976392 G>A with cancer risk. However, the conclusions were inconsistent. Therefore, we performed a meta-analysis to elucidate whether there is a true association, or artifact. We systematically searched eligible studies from MEDLINE, EMBASE and CBM database. Odds ratios and 95% confidence intervals were used to evaluate the strength of the association. The final analysis included 32 studies consisting of 30028 cases and 38765 controls for the rs2294008 C>T polymorphism, and 14 studies with 8190 cases and 7176 controls for the rs2976392 G>A polymorphism. Consequently, the PSCA rs2294008 C>T polymorphism was significantly associated with increased overall cancer risk. Further stratifications indicated the increased risk was more pronounced for gastric (diffused type and non-gastric cardia adenocarcinoma) and bladder cancer. A similar association was observed for the rs2976392 G>A polymorphism. This meta-analysis demonstrated that both of the PSCA rs2294008 C>T and rs2976392 G>A polymorphisms are associated with increased cancer risk, especially for gastric cancer and bladder cancer. Further large-scale studies with different ethnicities and subtypes of gastric cancer are required to confirm the results from this meta-analysis.
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Affiliation(s)
- Yong Gu
- Department of Thoracic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Qiang-Sheng Dai
- Department of Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Rui-Xi Hua
- Department of Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Bing Zhang
- Department of Medical Imaging, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jin-Hong Zhu
- Molecular Epidemiology Laboratory and Laboratory Medicine, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Jian-Wen Huang
- Department of Radiotherapy, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Bin-Hui Xie
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Shi-Qiu Xiong
- Department of Biochemistry, University of Leicester, Leicester, UK
| | - Guo-Sheng Tan
- Department of Medical Imaging, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - He-Ping Li
- Department of Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.,Department of Medical Imaging, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
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Loss-of-function variants in ATM confer risk of gastric cancer. Nat Genet 2015; 47:906-10. [PMID: 26098866 DOI: 10.1038/ng.3342] [Citation(s) in RCA: 126] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Accepted: 05/29/2015] [Indexed: 12/18/2022]
Abstract
Gastric cancer is a serious health problem worldwide, with particularly high prevalence in eastern Asia. Genome-wide association studies (GWAS) in Asian populations have identified several loci that associate with gastric cancer risk. Here we report a GWAS of gastric cancer in a European population, using information on 2,500 population-based gastric cancer cases and 205,652 controls. We found a new gastric cancer association with loss-of-function mutations in ATM (gene test, P = 8.0 × 10(-12); odds ratio (OR) = 4.74). The combination of the loss-of-function variants p.Gln852*, p.Ser644* and p.Tyr103* (combined minor allele frequency (MAF) = 0.3%) also associates with pancreatic and prostate cancers (OR = 3.81 and 2.18, respectively) and gives an indication of risk of breast and colorectal cancers (OR = 1.82 and 1.97, respectively). Cancers in those carrying loss-of-function ATM mutations are diagnosed at a significantly earlier age than in non-carriers. Our results confirm an association between gastric cancer in Europeans and three loci previously reported in Asians, MUC1, PRKAA1 and PSCA, refine the association signal at PRKAA1 and support a pathogenic role for the tandem repeat identified in MUC1.
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Ichikawa H, Sugimoto M, Uotani T, Sahara S, Yamade M, Iwaizumi M, Yamada T, Osawa S, Sugimoto K, Miyajima H, Yamaoka Y, Furuta T. Influence of prostate stem cell antigen gene polymorphisms on susceptibility to Helicobacter pylori-associated diseases: a case-control study. Helicobacter 2015; 20:106-13. [PMID: 25582162 DOI: 10.1111/hel.12183] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Patients with duodenal ulcer have a reduced risk of developing gastric cancer compared to those without. Recently, the prostate stem cell antigen (PSCA) rs2294008 C>T polymorphism was found to be associated with different pathogenesis of duodenal ulcer and gastric cancer developments. However, whether PSCA rs2294008 C>T polymorphism is associated with severity of gastric mucosal atrophy is unclear. We examined the influence of the PSCA rs2294008 C>T polymorphism on susceptibility to H. pylori-related diseases and the relationships between PSCA polymorphism and gastric mucosal atrophy. METHODS PSCA rs2294008 C>T polymorphism was assessed in H. pylori-positive Japanese patients (n = 488) with noncardia gastric cancer (n = 193), gastric ulcer (n = 84), duodenal ulcer (n = 61), and atrophic gastritis (n = 150), as well as in H. pylori-negatives (n = 266). RESULTS Frequency of PSCA rs2294008 C/C genotype in duodenal ulcer was 36.1%, which was significantly higher than those with gastric cancer (12.4%), gastric ulcer (19.0%), gastritis (10.7%), and H. pylori-negatives (19.5%) (p < .001). Compared with duodenal ulcer, having the T allele significantly increased the risk of gastric cancer (OR: 3.97, 95% CI: 2.02-7.80; p < .001), gastric ulcer (2.40, 1.13-5.10; p = .023), and gastritis (4.72, 2.26-9.86; p < .001). Mean pepsinogen (PG) I/PG II ratio in T allele carriers (2.17 ± 0.75) was significantly lower than that in C/C genotype (3.39 ± 1.27, p < .001). CONCLUSIONS The PSCA rs2294008 C>T polymorphism is associated with differing susceptibilities to H. pylori-associated diseases. The PSCA rs2294008 C>T polymorphism may be acting through induction of gastric mucosal atrophy, finally leading to development of gastric ulcer and gastric cancer in PSCA rs2294008 T allele carriers, but not duodenal ulcer.
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Affiliation(s)
- Hitomi Ichikawa
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
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García-González MA, Bujanda L, Quintero E, Santolaria S, Benito R, Strunk M, Sopeña F, Thomson C, Pérez-Aisa A, Nicolás-Pérez D, Hijona E, Carrera-Lasfuentes P, Piazuelo E, Jiménez P, Espinel J, Campo R, Manzano M, Geijo F, Pellise M, Zaballa M, González-Huix F, Espinós J, Titó L, Barranco L, Pazo-Cid R, Lanas A. Association ofPSCArs2294008 gene variants with poor prognosis and increased susceptibility to gastric cancer and decreased risk of duodenal ulcer disease. Int J Cancer 2015; 137:1362-73. [PMID: 25721731 DOI: 10.1002/ijc.29500] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Accepted: 02/18/2015] [Indexed: 12/13/2022]
Affiliation(s)
- María Asunción García-González
- Instituto De Investigación Sanitaria Aragón (IIS Aragón); Zaragoza Spain
- CIBER De Enfermedades Hepáticas Y Digestivas (CIBERehd); Zaragoza Spain
| | - Luis Bujanda
- CIBER De Enfermedades Hepáticas Y Digestivas (CIBERehd); Zaragoza Spain
- Department of Gastroenterology; Hospital Donostia/Instituto Biodonostia, Universidad Del País Vasco (UPV/EHU); San Sebastián Spain
| | - Enrique Quintero
- Department of Gastroenterology; Hospital Universitario De Canarias, Instituto Universitario De Tecnologías Biomédicas (ITB), Centro De Investigación Biomédica De Canarias (CIBICAN); Tenerife Spain
| | | | - Rafael Benito
- CIBER De Enfermedades Hepáticas Y Digestivas (CIBERehd); Zaragoza Spain
- Department of Microbiology; Faculty of Medicine; Hospital Clínico Universitario; Zaragoza Spain
| | - Mark Strunk
- Instituto De Investigación Sanitaria Aragón (IIS Aragón); Zaragoza Spain
- CIBER De Enfermedades Hepáticas Y Digestivas (CIBERehd); Zaragoza Spain
| | - Federico Sopeña
- CIBER De Enfermedades Hepáticas Y Digestivas (CIBERehd); Zaragoza Spain
- Department of Gastroenterology; Hospital Clínico Universitario Lozano Blesa; Zaragoza Spain
| | - Concha Thomson
- Department of Gastroenterology; Hospital Obispo Polanco; Teruel Spain
| | | | - David Nicolás-Pérez
- Department of Gastroenterology; Hospital Universitario De Canarias, Instituto Universitario De Tecnologías Biomédicas (ITB), Centro De Investigación Biomédica De Canarias (CIBICAN); Tenerife Spain
| | - Elizabeth Hijona
- Department of Gastroenterology; Hospital Donostia/Instituto Biodonostia, Universidad Del País Vasco (UPV/EHU); San Sebastián Spain
| | | | - Elena Piazuelo
- Instituto De Investigación Sanitaria Aragón (IIS Aragón); Zaragoza Spain
- CIBER De Enfermedades Hepáticas Y Digestivas (CIBERehd); Zaragoza Spain
| | - Pilar Jiménez
- CIBER De Enfermedades Hepáticas Y Digestivas (CIBERehd); Zaragoza Spain
| | - Jesús Espinel
- Department of Gastroenterology; Complejo Hospitalario; León Spain
| | - Rafael Campo
- Department of Gastroenterology; Hospital Parc Tauli; Sabadell Spain
| | - Marisa Manzano
- Department of Gastroenterology; Hospital 12 De Octubre; Madrid Spain
| | - Fernando Geijo
- Department of Gastroenterology; Hospital Clínico Universitario; Salamanca Spain
| | - María Pellise
- Department of Gastroenterology; Hospital Clinic I Provincial; Barcelona Spain
| | - Manuel Zaballa
- Department of Gastroenterology; Hospital De Cruces; Barakaldo Spain
| | | | - Jorge Espinós
- Department of Gastroenterology; Mutua De Tarrasa; Spain
| | - Llúcia Titó
- Department of Gastroenterology; Hospital De Mataró; Mataró Spain
| | - Luis Barranco
- Department of Gastroenterology; Hospital Del Mar; Barcelona Spain
| | | | - Angel Lanas
- Instituto De Investigación Sanitaria Aragón (IIS Aragón); Zaragoza Spain
- CIBER De Enfermedades Hepáticas Y Digestivas (CIBERehd); Zaragoza Spain
- Department of Gastroenterology; Hospital Clínico Universitario Lozano Blesa; Zaragoza Spain
- Department of Medicine; Universidad de Zaragoza; Spain
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Saeki N, Ono H, Yanagihara K, Aoyagi K, Sasaki H, Sakamoto H, Yoshida T. rs2294008T, a risk allele for gastric and gallbladder cancers, suppresses the PSCA promoter by recruiting the transcription factor YY1. Genes Cells 2015; 20:382-91. [PMID: 25727947 DOI: 10.1111/gtc.12228] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2014] [Accepted: 12/31/2014] [Indexed: 12/12/2022]
Abstract
Previous genomewide association studies identified prostate stem cell antigen (PSCA) as a gastric cancer (GC) susceptibility gene and showed an association between GC and the T allele of the single nucleotide polymorphism rs2294008 (C/T) in this gene. The protein product of this gene inhibits cell growth, and the T allele significantly suppresses the transcriptional activity of the -3.2 kb PSCA upstream region. However, the mechanism remains unknown. In this study, we conducted reporter assays using the PSCA upstream region containing the C allele and identified the region from -200 to +38 bp of the transcription initiation site of the gene as a critical region of the -3.2 kb PSCA upstream region. We found that introducing the T allele at rs2294008 generated a consensus binding sequence for the Polycomb group transcription factor Yin Yang 1 (YY1) and that disruption of the consensus sequence restored the transcriptional activity to the -3.2 kb PSCA upstream region. These findings imply that the T allele significantly suppresses PSCA expression in vivo by recruiting YY1 to its promoter, which eventually predisposes gastric epithelial cells to GC development.
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Affiliation(s)
- Norihisa Saeki
- Division of Genetics, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan
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Duell EJ, Bonet C, Muñoz X, Lujan-Barroso L, Weiderpass E, Boutron-Ruault MC, Racine A, Severi G, Canzian F, Rizzato C, Boeing H, Overvad K, Tjønneland A, Argüelles M, Sánchez-Cantalejo E, Chamosa S, Huerta JM, Barricarte A, Khaw KT, Wareham N, Travis RC, Trichopoulou A, Trichopoulos D, Yiannakouris N, Palli D, Agnoli C, Tumino R, Naccarati A, Panico S, Bueno-de-Mesquita HB, Siersema PD, Peeters PHM, Ohlsson B, Lindkvist B, Johansson I, Ye W, Johansson M, Fenger C, Riboli E, Sala N, González CA. Variation at ABO histo-blood group and FUT loci and diffuse and intestinal gastric cancer risk in a European population. Int J Cancer 2015; 136:880-93. [PMID: 24947433 DOI: 10.1002/ijc.29034] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Accepted: 05/16/2014] [Indexed: 12/12/2022]
Abstract
ABO blood serotype A is known to be associated with risk of gastric cancer (GC), but little is known how ABO alleles and the fucosyltransferase (FUT) enzymes and genes which are involved in Lewis antigen formation [and in Helicobacter pylori (H. pylori) binding and pathogenicity] may be related to GC risk in a European population. The authors conducted an investigation of 32 variants at ABO and FUT1-7 loci and GC risk in a case-control study of 365 cases and 1,284 controls nested within the EPIC cohort (the EPIC-Eurgast study). Four variants (including rs505922) in ABO, and allelic blood group A (AO+AA, odds ratio=1.84, 95%CI=1.20-2.80) were associated with diffuse-type GC; however, conditional models with other ABO variants indicated that the associations were largely due to allelic blood group A. One variant in FUT5 was also associated with diffuse-type GC, and four variants (and haplotypes) in FUT2 (Se), FUT3 (Le) and FUT6 with intestinal-type GC. Further, one variant in ABO, two in FUT3 and two in FUT6 were associated with H. pylori infection status in controls, and two of these (in FUT3 and FUT6) were weakly associated with intestinal-type GC risk. None of the individual variants surpassed a Bonferroni corrected p-value cutoff of 0.0016; however, after a gene-based permutation test, two loci [FUT3(Le)/FUT5/FUT6 and FUT2(Se)] were significantly associated with diffuse- and intestinal-type GC, respectively. Replication and functional studies are therefore recommended to clarify the role of ABO and FUT alleles in H. pylori infection and subtype-specific gastric carcinogenesis.
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Affiliation(s)
- Eric J Duell
- Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain
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Wang M, Wang XJ, Ma YF, Ma XB, Dai ZM, Lv Y, Lin S, Liu XH, Yang PT, Dai ZJ. PSCA rs2294008 C > T polymorphism contributes to gastric and bladder cancer risk. Ther Clin Risk Manag 2015; 11:237-45. [PMID: 25709466 PMCID: PMC4335611 DOI: 10.2147/tcrm.s77089] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background Previous studies suggested genetic variations in PSCA (prostate stem cell antigen) may confer the susceptibility of cancer. Many case–control studies have reported the relationship between PSCA rs2294008 C > T polymorphism and cancer, especially gastric cancer and bladder cancer. However, the results are inconsistent. This meta-analysis is aimed at evaluating the association of rs2294008 polymorphism with cancer risk. Methods The databases of PubMed, ISI Web of Knowledge, EMBASE, and Chinese National Knowledge Infrastructure (CNKI) were searched for related publications. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the strength of the associations. Fixed models were used when heterogeneity among studies was not detected, otherwise the random model was used. Results Twenty-six studies from 24 articles with 30,050 multiple cancer cases and 51,670 controls were pooled into this meta-analysis. The results showed that the rs2294008 polymorphism was associated with increased cancer risk in any genetic model (T vs C, OR: 1.18, 95% CI: 1.08–1.28; TT vs CC, OR: 1.36, 95% CI: 1.14–1.62; TC vs CC, OR: 1.29, 95% CI: 1.17–1.44; TT + TC vs CC, OR: 1.32, 95% CI: 1.18–1.49; TT vs TC + CC, OR: 1.15, 95% CI: 1.02–1.30). In stratified analysis by cancer type, we found that the T allele had a significant high risk of gastric and bladder cancer, but not in other cancers. In subgroup analysis by ethnicity, increased cancer risk was found in both Asians and Caucasians. Conclusion Our study suggested that the PSCA rs2294008 C > T polymorphism is a risk factor for cancer, especially in gastric and bladder cancer.
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Affiliation(s)
- Meng Wang
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Xi-Jing Wang
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Yun-Feng Ma
- Department of Immunology and Pathogenic Biology, Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Xiao-Bin Ma
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Zhi-Ming Dai
- Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Ye Lv
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Shuai Lin
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Xing-Han Liu
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Peng-Tao Yang
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Zhi-Jun Dai
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China ; Center for Translational Medicine, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, People's Republic of China
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Sun H, Wu X, Wu F, Li Y, Yu Z, Chen X, Chen Y, Yang W. Associations of genetic variants in the PSCA, MUC1 and PLCE1 genes with stomach cancer susceptibility in a Chinese population. PLoS One 2015; 10:e0117576. [PMID: 25658482 PMCID: PMC4319726 DOI: 10.1371/journal.pone.0117576] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Accepted: 12/27/2014] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Several genetic variants including PSCA rs2294008 C>T and rs2976392 G>A, MUC1 rs4072037 T>C, and PLCE1 rs2274223 A>G have shown significant association with stomach cancer risk in the previous genome-wide association studies (GWASs). METHODS To evaluate associations of these SNPs in the Han Chinese, an independent hospital based case-control study was performed by genotyping these four polymorphisms in a total of 692 stomach cancer cases and 774 healthy controls acquired by using frequency matching for age and gender. False-positive report probability (FPRP) analysis was also performed to validate all statistically significant findings. RESULTS In the current study, significant association with stomach cancer susceptibility was observed for all the four polymorphisms of interest. Specifically, a significant increased stomach cancer risk was associated with PSCA rs2294008 (CT vs. CC: adjusted OR = 1.37, 95% CI = 1.07-1.74, and CT/TT vs.CC: adjusted OR = 1.30, 95% CI = 1.03-1.63), PSCA rs2976392 (AG vs. GG: adjusted OR = 1.30, 95% CI = 1.02-1.65, and AG/AA vs. GG: adjusted OR = 1.26, 95% CI = 1.00-1.59), or PLCE1 rs2274223 (AG vs. AA: adjusted OR = 1.48, 95% CI = 1.15-1.90, and AG/GG vs. AA: adjusted OR = 1.45, 95% CI = 1.14-1.84), respectively. In contrast, MUC1 rs4072037 was shown to decrease the cancer risk (CT vs. TT: adjusted OR = 0.77, 95% CI = 0.60-0.98). Patients with more than one risk genotypes had significant increased risk to develop stomach cancer (adjusted OR = 1.30, 95% CI = 1.03-1.64), when compared with those having 0-1 risk genotypes. Stratified analysis indicated that the increased risk was more pronounced in younger subjects, men, ever smokers, smokers with pack years ≤ 27, patients with high BMI, or non-cardia stomach cancer. CONCLUSIONS This study substantiated the associations between four previous reported genetic variants and stomach cancer susceptibility in an independent Han Chinese population. Further studies with larger sample size and different ethnicities are warranted to validate our findings.
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Affiliation(s)
- Hongwei Sun
- Department of Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - Xiaoli Wu
- Department of Gastroenterology, First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - Fang Wu
- Department of Gastroenterology, First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - Ying Li
- Department of Operating room, First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - Zhengping Yu
- Department of Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - Xiangrong Chen
- Department of Gastroenterology, First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - Yunzhi Chen
- Department of Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - Wenjun Yang
- Department of Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
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Zheng K, Chen Z, Tian Y, Hao G. Association between PSCA mRNA expression levels and rs2294008 polymorphism in transitional cell cancer of the bladder. Oncol Lett 2015; 9:557-562. [PMID: 25624885 PMCID: PMC4301555 DOI: 10.3892/ol.2014.2734] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2014] [Accepted: 10/15/2014] [Indexed: 12/21/2022] Open
Abstract
Prostate stem cell antigen (PSCA) was originally identified as a gene that is overexpressed in prostate cancer, and correlates with prostate cancer progression and prognosis. Recently, a significant association has been identified between the PSCA rs2294008 (C>T) polymorphism and the risk of developing bladder cancer. Therefore, the present study investigated the different expression levels of PSCA mRNA in transitional cell carcinoma (TCC) of the bladder and normal bladder tissue. Furthermore, the association between PSCA mRNA expression levels in TCC and different rs2294008 (C>T) genotypes and various clinicopathological features, including tumor stage and grade, were evaluated. Reverse transcription-quantitative polymerase chain reaction was performed on 80 TCC samples and 38 samples of normal bladder urothelium from TCC patients who underwent transurethral resection of bladder tumor or radical cystectomy at the Beijing Friendship Hospital (Beijing, China) between September 2010 and May 2011. Genomic DNA was extracted from tumor tissue and sequenced to determine the rs2294008 (C>T) genotype. PSCA mRNA expression was detected in all samples (100%); however, tumor samples exhibited significantly higher PSCA expression levels compared with the normal urothelium samples (P=0.038). PSCA mRNA expression was positively correlated with the histological grade of the tumor (G1-2 vs. G3; P=0.001); however, no significant difference was detected between patients with superficial (Ta or T1) and muscle-invasive (≥pT2) tumors (P=0.250). Thus, PSCA mRNA expression levels were associated with TCC and tumor histological grade, but not the tumor stage. Additionally, PSCA mRNA expression levels were significantly higher in T allele carriers compared with CC homozygous patients (P=0.001), indicating that the presence of the T allele may increase PSCA mRNA expression. Therefore, rs2294008 (C>T) may be associated with the biological properties of TCC and, thus, future research should focus on the physiological function of PSCA and the mechanism of rs2294008.
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Affiliation(s)
- Kewen Zheng
- Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China ; Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, P.R. China
| | - Zhigang Chen
- Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China ; Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, P.R. China
| | - Ye Tian
- Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Gangyue Hao
- Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
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Espinosa-Parrilla Y, Muñoz X, Bonet C, Garcia N, Venceslá A, Yiannakouris N, Naccarati A, Sieri S, Panico S, Huerta JM, Barricarte A, Menéndez V, Sánchez-Cantalejo E, Dorronsoro M, Brennan P, Duarte-Salles T, B As Bueno-de-Mesquita H, Weiderpass E, Lund E, Clavel-Chapelon F, Boutron-Ruault MC, Racine A, Numans ME, Tumino R, Canzian F, Campa D, Sund M, Johansson M, Ohlsson B, Lindkvist B, Overvad K, Tjønneland A, Palli D, Travis RC, Khaw KT, Wareham N, Boeing H, Nesi G, Riboli E, Gonzalez CA, Sala N. Genetic association of gastric cancer with miRNA clusters including the cancer-related genes MIR29, MIR25, MIR93 and MIR106: results from the EPIC-EURGAST study. Int J Cancer 2014; 135:2065-76. [PMID: 24643999 DOI: 10.1002/ijc.28850] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 01/24/2014] [Accepted: 01/28/2014] [Indexed: 12/12/2022]
Abstract
MicroRNAs (miRNAs) are post-transcriptional gene regulators involved in a wide range of biological processes including tumorigenesis. Deregulation of miRNA pathways has been associated with cancer but the contribution of their genetic variability to this disorder is poorly known. We analyzed the genetic association of gastric cancer (GC) and its anatomical and histological subtypes, with 133 single-nucleotide polymorphisms (SNPs) tagging 15 isolated miRNAs and 24 miRNA clusters potentially involved in cancer, in 365 GC cases and 1,284 matched controls within the European Prospective Investigation into Cancer and Nutrition cohort. Various SNPs were associated with GC under the log-additive model. Furthermore, several of these miRNAs passed the gene-based permutation test when analyzed according to GC subtypes: three tagSNPs of the miR-29a/miR-29b-1 cluster were associated with diffuse subtype (minimum p-value = 1.7 × 10(-4) ; odds ratio, OR = 1.72; 95% confidence interval, CI = 1.30-2.28), two tagSNPs of the miR-25/miR-93/miR-106b cluster were associated with cardia GC (minimum p-value = 5.38 × 10(-3) ; OR = 0.56, 95% CI = 0.37-0.86) and one tagSNP of the miR-363/miR-92a-2/miR-19b-2/miR-20b/miR-18b/miR-106a cluster was associated with noncardia GC (minimum p-value = 5.40 × 10(-3) ; OR = 1.41, 95% CI = 1.12-1.78). Some functionally validated target genes of these miRNAs are implicated in cancer-related processes such as methylation (DNMT3A, DNMT3B), cell cycle (E2F1, CDKN1A, CDKN1C), apoptosis (BCL2L11, MCL1), angiogenesis (VEGFA) and progression (PIK3R1, MYCN). Furthermore, we identified genetic interactions between variants tagging these miRNAs and variants in their validated target genes. Deregulation of the expression of these miRNAs in GC also supports our findings, altogether suggesting for the fist time that genetic variation in MIR29, MIR25, MIR93 and MIR106b may have a critical role in genetic susceptibility to GC and could contribute to the molecular mechanisms of gastric carcinogenesis.
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Affiliation(s)
- Yolanda Espinosa-Parrilla
- Institut de Biologia Evolutiva, CSIC-Universitat Pompeu Fabra, Departament de Ciències Experimentals i de la Salut, UPF, Barcelona, Spain; Programa de Genética Humana, ICBM, Facultad de Medicina, Universidad de Chile, Santiago de Chile, Chile
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Abstract
Gastric cancer remains highly prevalent and accounts for a notable proportion of global cancer mortality. This cancer is also associated with poor survival rates. Understanding the genetic basis of gastric cancer will offer insights into its pathogenesis, help identify new biomarkers and novel treatment targets, aid prognostication and could be central to developing individualized treatment strategies in the future. An inherited component contributes to <3% of gastric cancers; the majority of genetic changes associated with gastric cancer are acquired. Over the past few decades, advances in technology and high-throughput analysis have improved understanding of the molecular aspects of the pathogenesis of gastric cancer. These aspects are multifaceted and heterogeneous and represent a wide spectrum of several key genetic influences, such as chromosomal instability, microsatellite instability, changes in microRNA profile, somatic gene mutations or functional single nucleotide polymorphisms. These genetic aspects of the pathogenesis of gastric cancer will be addressed in this Review.
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Affiliation(s)
- Mairi H McLean
- National Cancer Institute, Laboratory of Molecular Immunoregulation, Cancer &Inflammation Program, 1050 Boyles Street, Frederick, MD 21702-1201, USA
| | - Emad M El-Omar
- Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB51 5ER, UK
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Durães C, Muñoz X, Bonet C, García N, Venceslá A, Carneiro F, Peleteiro B, Lunet N, Barros H, Lindkvist B, Boutron-Ruault MC, Bueno-de-Mesquita HB, Rizzato C, Trichopoulou A, Weiderpass E, Naccarati A, Travis RC, Tjønneland A, Gurrea AB, Johansson M, Riboli E, Figueiredo C, González CA, Capellà G, Machado JC, Sala N. Genetic variants in the IL1A gene region contribute to intestinal-type gastric carcinoma susceptibility in European populations. Int J Cancer 2014; 135:1343-55. [PMID: 24615437 DOI: 10.1002/ijc.28776] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2013] [Revised: 12/27/2013] [Accepted: 01/16/2014] [Indexed: 12/11/2022]
Abstract
The most studied genetic susceptibility factors involved in gastric carcinoma (GC) risk are polymorphisms in the inflammation-linked genes interleukin 1 (IL1) B and IL1RN. Despite the evidence pointing to the IL1 region, definite functional variants reproducible across populations of different genetic background have not been discovered so far. A high density linkage disequilibrium (LD) map of the IL1 gene cluster was established using HapMap to identify haplotype tagSNPs. Eighty-seven SNPs were genotyped in a Portuguese case-control study (358 cases, 1,485 controls) for the discovery analysis. A replication study, including a subset of those tagSNPs (43), was performed in an independent analysis (EPIC-EurGast) containing individuals from 10 European countries (365 cases, 1284 controls). Single SNP and haplotype block associations were determined for GC overall and anatomopathological subtypes. The most robust association was observed for SNP rs17042407, 16Kb upstream of the IL1A gene. Although several other SNP associations were observed, only the inverse association of rs17042407 allele C with GC of the intestinal type was observed in both studies, retaining significance after multiple testing correction (p = 0.0042) in the combined analysis. The haplotype analysis of the IL1A LD block in the combined dataset revealed the association between a common haplotype carrying the rs17042407 variant and GC, particularly of the intestinal type (p = 3.1 × 10(-5) ) and non cardia localisation (p = 4.6 × 10(-3) ). These results confirm the association of IL1 gene variants with GC and reveal a novel SNP and haplotypes in the IL1A region associated with intestinal type GC in European populations.
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Affiliation(s)
- Cecília Durães
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
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Zuo L, Zhang LF, Wu XP, Zhou ZX, Zou JG, He J, Hou JQ. Association of a common genetic variant in prostate stem cell antigen with cancer risk. Arch Med Sci 2014; 10:425-33. [PMID: 25097570 PMCID: PMC4107248 DOI: 10.5114/aoms.2014.43736] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2012] [Revised: 11/21/2012] [Accepted: 01/06/2013] [Indexed: 01/12/2023] Open
Abstract
INTRODUCTION Polymorphisms in the prostate stem cell antigen (PSCA) gene have been hypothesized to increase the genetic susceptibility to cancers. The common sequence variation in PSCA rs2294008 (C>T) has been implicated in cancer risk. However, results of the relevant published studies were somewhat underpowered and controversial in general. MATERIAL AND METHODS To evaluate the role of PSCA rs2294008 (C>T) genotype in global cancer, we performed a pooled analysis of all the available published studies involving 22,817 cancer patients and 27,753 control subjects. RESULTS The results showed evidence that PSCA rs2294008 (C>T) was associated with increased total cancer risk in the overall comparisons. Stratified analysis by cancer type indicated that PSCA rs2294008 T is associated with increased risk of gastric cancer (OR = 1.24, 95% CI = 1.09-1.42, p heterogeneity < 0.001, I (2) = 88.0%) and bladder cancer (OR = 1.07, 95% CI = 1.04-1.11, p heterogeneity = 0.108, I (2) = 55.0%) by allelic contrast. Furthermore, in stratified analysis by histological types of gastric cancer, this PSCA variant showed significant associations with diffuse type (OR = 1.81, 95% CI = 1.16-2.81, p heterogeneity < 0.001, I (2) = 88.9%) but not intestinal type (OR = 1.29, 95% CI = 0.95-1.74, p heterogeneity < 0.001, I (2) = 85.2%) in a dominant genetic model. Similar results were found in Asian and European descendents and population-based studies. CONCLUSIONS In all, our meta-analysis suggests that PSCA rs2294008 (C>T) may play allele-specific roles in cancer development. Further prospective studies with larger numbers of participants worldwide should be performed in different kinds of cancer and other descendents in more detail.
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Affiliation(s)
- Li Zuo
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Department of Urology, Changzhou No. 2 People's Hospital Affiliated to Nanjing Medical University, Changzhou, China
| | - Li Feng Zhang
- Department of Urology, Changzhou No. 2 People's Hospital Affiliated to Nanjing Medical University, Changzhou, China
| | - Xiao Peng Wu
- Department of Urology, Changzhou No. 2 People's Hospital Affiliated to Nanjing Medical University, Changzhou, China
| | - Zhong Xing Zhou
- Department of Urology, Changzhou No. 2 People's Hospital Affiliated to Nanjing Medical University, Changzhou, China
| | - Jian Gang Zou
- Department of Urology, Changzhou No. 2 People's Hospital Affiliated to Nanjing Medical University, Changzhou, China
| | - Jun He
- Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jian Quan Hou
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
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Sun Y, Gu J, Ajani JA, Chang DW, Wu X, Stroehlein JR. Genetic and intermediate phenotypic susceptibility markers of gastric cancer in Hispanic Americans: a case-control study. Cancer 2014; 120:3040-8. [PMID: 24962126 DOI: 10.1002/cncr.28792] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Revised: 03/27/2014] [Accepted: 04/01/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hispanics are the largest nonwhite ethnic group in the US population, and they have higher incidence and mortality rates for gastric cancer (GC) than whites and Asians. Studies have identified several genetic susceptibility loci and intermediate phenotypic biomarkers for GC in whites and Asians. No studies have evaluated genetic susceptibility and intermediate phenotypic biomarkers in Hispanics. METHODS In a case-control study of 132 Hispanic patients with GC (cases) and a control group of 125 Hispanics (controls), the authors evaluated the association of 5 single nucleotide polymorphisms (SNPs) that predispose whites and/or Asians to GC and of 2 intermediate phenotypic markers in peripheral blood leukocytes, ie, telomere length and mitochondrial DNA (mtDNA) copy number, with the GC risk. RESULTS The variant C allele of the reference SNP rs2294008 in the PSCA gene was associated with a significantly reduced risk of GC (per allele-adjusted odds ratio [aOR], 0.51; 95% confidence interval [CI], 0.33-0.77; P = .002). Leukocyte mtDNA copy numbers were significantly lower in GC cases (mean ± standard deviation, 0.91 ± 0.28) than in controls (1.29 ± 0.42; P < .001). When individuals were dichotomized into high and low mtDNA copy number groups based on the median mtDNA copy number value in the controls, those who had a low mtDNA copy number had a significantly increased risk of GC (aOR, 11.00; 95% CI, 4.79-25.23; P < .001) compared with those who had a high mtDNA copy number. Telomere length was not associated significantly with the risk of GC (aOR, 1.21; 95% CI, 0.65-2.27; P = .551). CONCLUSIONS Hispanics share certain genetic susceptibility loci and intermediate phenotypic GC biomarkers with whites and Asians and may also have distinct genetic susceptibility factors.
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Affiliation(s)
- Yuhui Sun
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Obstetrics and Gynecology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
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Saeki N, Sakamoto H, Yoshida T. Mucin 1 gene (MUC1) and gastric-cancer susceptibility. Int J Mol Sci 2014; 15:7958-73. [PMID: 24810688 PMCID: PMC4057712 DOI: 10.3390/ijms15057958] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Revised: 04/11/2014] [Accepted: 04/21/2014] [Indexed: 12/22/2022] Open
Abstract
Gastric cancer (GC) is one of the major malignant diseases worldwide, especially in Asia. It is classified into intestinal and diffuse types. While the intestinal-type GC (IGC) is almost certainly caused by Helicobacter pylori (HP) infection, its role in the diffuse-type GC (DGC) appears limited. Recently, genome-wide association studies (GWAS) on Japanese and Chinese populations identified chromosome 1q22 as a GC susceptibility locus which harbors mucin 1 gene (MUC1) encoding a cell membrane-bound mucin protein. MUC1 has been known as an oncogene with an anti-apoptotic function in cancer cells; however, in normal gastric mucosa, it is anticipated that the mucin 1 protein has a role in protecting gastric epithelial cells from a variety of external insults which cause inflammation and carcinogenesis. HP infection is the most definite insult leading to GC, and a protective function of mucin 1 protein has been suggested by studies on Muc1 knocked-out mice.
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Affiliation(s)
- Norihisa Saeki
- Division of Genetics, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan.
| | - Hiromi Sakamoto
- Division of Genetics, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan.
| | - Teruhiko Yoshida
- Division of Genetics, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan.
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Chiurillo MA. Role of gene polymorphisms in gastric cancer and its precursor lesions: Current knowledge and perspectives in Latin American countries. World J Gastroenterol 2014; 20:4503-4515. [PMID: 24782603 PMCID: PMC4000487 DOI: 10.3748/wjg.v20.i16.4503] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 12/23/2013] [Accepted: 03/13/2014] [Indexed: 02/07/2023] Open
Abstract
Latin America shows one of the highest incidence rates of gastric cancer in the world, with variations in mortality rates among nations or even within countries belonging to this region. Gastric cancer is the result of a multifactorial complex process, for which a multistep model of carcinogenesis is currently accepted. Additionally to the infection with Helicobacter pylori, that plays a major role, environmental factors as well as genetic susceptibility factors are significant players at different stages in the gastric cancer process. The differences in population origin, demographic structure, socio-economic development, and the impact of globalization lifestyles experienced in Latin America in the last decades, all together offer opportunities for studying in this context the influence of genetic polymorphisms in the susceptibility to gastric cancer. The aim of this article is to discuss current trends on gastric cancer in Latin American countries and to review the available published information about studies of association of gene polymorphisms involved in gastric cancer susceptibility from this region of the world. A total of 40 genes or genomic regions and 69 genetic variants, 58% representing markers involved in inflammatory response, have been used in a number of studies in which predominates a low number of individuals (cases and controls) included. Polymorphisms of IL-1B (-511 C/T, 14 studies; -31 T/C, 10 studies) and IL-1RN (variable number of tandem repeats, 17 studies) are the most represented ones in the reviewed studies. Other genetic variants recently evaluated in large meta-analyses and associated with gastric cancer risk were also analyzed in a few studies [e.g., prostate stem cell antigen (PSCA), CDH1, Survivin]. Further and better analysis centered in gene polymorphisms linked to other covariates, epidemiological studies and the information provided by meta-analyses and genome-wide association studies should help to improve our understanding of gastric cancer etiology in order to develop appropriate health programs in Latin America.
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Yang X, Guo Z, Liu Y, Si T, Yu H, Li B, Tian W. Prostate stem cell antigen and cancer risk, mechanisms and therapeutic implications. Expert Rev Anticancer Ther 2014; 14:31-37. [PMID: 24308679 DOI: 10.1586/14737140.2014.845372] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2023]
Abstract
Prostate stem cell antigen (PSCA) was originally identified as a tumor antigen in prostate cancer. Recent studies indicated that PSCA was correlated with many cancer types. In this review, we will consider the origin of PSCA, discuss the expression of PSCA in normal and cancer tissue, describe PSCA polymorphisms and cancer risk, summarize potential mechanisms for PSCA involvement in cancer; and look into the therapeutic implications of PSCA. PSCA is upregulated in prostate cancer, pancreatic cancer and bladder cancer, as well as a number of others, making it an ideal clinical target for both diagnosis and therapy. Future studies will be required to explore its mechanisms on various cancer types, and to confirm its clinical utility for diagnosis and immunotherapy strategies. The study of PSCA regulation and expression may also provide information on normal prostate development and prostate carcinogenesis.
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Affiliation(s)
- Xueling Yang
- Department of Interventional Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
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Companioni O, Bonet C, Muñoz X, Weiderpass E, Panico S, Tumino R, Palli D, Agnoli C, Vineis P, Boutron-Ruault MC, Racine A, Clavel-Chapelon F, Travis RC, Khaw KT, Riboli E, Murphy N, Vergnaud AC, Trichopoulou A, Benetou V, Trichopoulos D, Lund E, Johansen D, Lindkvist B, Johansson M, Sund M, Ardanaz E, Sánchez-Cantalejo E, Huerta JM, Dorronsoro M, Ramón Quirós J, Tjonneland A, Mortensen LM, Overvad K, Chang-Claude J, Rizzato C, Boeing H, Bueno-de-Mesquita HB, Bueno de Mesquita HB, Siersema P, Peeters PHM, Numans ME, Carneiro F, Licaj I, Freisling H, Sala N, González CA. Polymorphisms of Helicobacter pylori signaling pathway genes and gastric cancer risk in the European Prospective Investigation into Cancer-Eurgast cohort. Int J Cancer 2014; 134:92-101. [PMID: 23824692 DOI: 10.1002/ijc.28357] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Accepted: 04/16/2013] [Indexed: 02/06/2023]
Abstract
Helicobacter pylori is a recognized causal factor of noncardia gastric cancer (GC). Lipopolysaccharide and peptidoglycan of this bacterium are recognized by CD14, TLR4 and NOD2 human proteins, while NFKB1 activates the transcription of pro-inflammatory cytokines to elicit an immune response. Single nucleotide polymorphisms (SNPs) in these genes have been associated with GC in different populations. We genotyped 30 SNPs of these genes, in 365 gastric adenocarcinomas and 1,284 matched controls from the European Prospective Investigation into Cancer cohort. The association with GC and its histological and anatomical subtypes was analyzed by logistic regression and corrected for multiple comparisons. Using a log-additive model, we found a significant association between SNPs in CD14, NOD2 and TLR4 with GC risk. However, after applying the multiple comparisons tests only the NOD2 region remained significant (p = 0.009). Analysis according to anatomical subtypes revealed NOD2 and NFKB1 SNPs associated with noncardia GC and CD14 SNPs associated with cardia GC, while analysis according to histological subtypes showed that CD14 was associated with intestinal but not diffuse GC. The multiple comparisons tests confirmed the association of NOD2 with noncardia GC (p = 0.0003) and CD14 with cardia GC (p = 0.01). Haplotype analysis was in agreement with single SNP results for NOD2 and CD14 genes. From these results, we conclude that genetic variation in NOD2 associates with noncardia GC while variation in CD14 is associated with cardia GC.
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Affiliation(s)
- Osmel Companioni
- Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology-IDIBELL, Barcelona, 08908, Spain
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Wang Q, Liu H, Xiong H, Liu Z, Wang LE, Qian J, Muddasani R, Lu V, Tan D, Ajani JA, Wei Q. Polymorphisms at the microRNA binding-site of the stem cell marker gene CD133 modify susceptibility to and survival of gastric cancer. Mol Carcinog 2013; 54:449-58. [PMID: 24302553 DOI: 10.1002/mc.22113] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2013] [Revised: 10/29/2013] [Accepted: 11/01/2013] [Indexed: 12/13/2022]
Abstract
CD133 is one of the most common stem cell markers, and functional single nucleotide polymorphisms (SNPs) of CD133 may modulate its gene functions and thus cancer risk and patient survival. We hypothesized that potentially functional CD133 SNPs are associated with gastric cancer (GC) risk and survival. To test this hypothesis, we conducted a case-control study of 371 GC patients and 313 cancer-free controls frequency-matched by age, sex, and ethnicity. We genotyped four selected, potentially functional CD133 SNPs (rs2240688A>C, rs7686732C>G, rs10022537T>A, and rs3130C>T) and used logistic regression analysis for associations of these SNPs with GC risk and Cox hazards regression analysis for survival. We found that compared with the miRNA binding site rs2240688 AA genotype, AC + CC genotypes were associated with significantly increased GC risk (adjusted OR = 1.52, 95% CI = 1.09-2.13); for another miRNA binding site rs3130C>T SNP, the TT genotype was associated with significantly reduced GC risk (adjusted OR = 0.68, 95% CI = 0.48-0.97), compared with CC + CT genotypes. In all patients, the risk rs3130 TT variant genotype was significantly associated with overall survival (OS) (adjusted P(trend) = 0.016 and 0.007 under additive and recessive models, respectively). These findings suggest that these two CD133 miRNA binding site variants, rs2240688 and rs3130, may be potential biomarkers for genetic susceptibility to GC and possible predictors for survival in GC patients but require further validation by larger studies.
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Affiliation(s)
- Qiming Wang
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China; Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
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Quantitative assessment of the influence of prostate stem cell antigen polymorphisms on gastric cancer risk. Tumour Biol 2013; 35:2167-74. [PMID: 24146278 DOI: 10.1007/s13277-013-1287-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2013] [Accepted: 10/02/2013] [Indexed: 02/08/2023] Open
Abstract
Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol-anchored 123-amino acid protein related to the cell proliferation inhibition and/or cell death induction activity which has attracted considerable attention as a candidate gene for gastric cancer (GC) since it was first identified through genome-wide association approach. Since then, the relationship between PSCA polymorphisms (rs2294008, rs2976392) and GC has been reported in various ethnic groups; however, these studies have yielded inconsistent results. To investigate this inconsistency, we performed a meta-analysis of 16 studies involving a total of 18,820 cases and 35,756 controls for the two widely studied polymorphisms of PSCA on genetic susceptibility for GC. Overall, the summary odds ratio for GC was 1.46 (95% CI 1.30-1.69, P < 10(-5)) and 1.49 (95% CI 1.22-1.82, P < 10(-4)) for PSCA rs2294008 and rs2976392 polymorphisms, respectively. Meanwhile, haplotype analyses of the two polymorphisms revealed a significant association between the combination of these alleles and GC risk. When stratifying for ethnicity, significantly increased risks were found for rs2294008 and rs2976392 polymorphism among East Asians in all genetic models, while no significant associations were observed for the rs2294008 polymorphism in Caucasians. In the stratified analyses according to histological type, and source of controls, evidence of gene-disease association was still obtained. In addition, our data indicate that rs2294008 of PSCA is involved in GC susceptibility and confer its effect primarily in noncardia tumors (OR = 1.30, 95% CI 1.12-1.53, P < 10(-4)). Our findings demonstrated that rs2294008 and rs2976392 polymorphism of PSCA is a risk-conferring factor associated with increased GC susceptibility, especially in East Asians.
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Rizzato C, Kato I, Plummer M, Muñoz N, Canzian F. Genetic variation in PSCA and risk of gastric advanced preneoplastic lesions and cancer in relation to Helicobacter pylori infection. PLoS One 2013; 8:e73100. [PMID: 24023815 PMCID: PMC3762831 DOI: 10.1371/journal.pone.0073100] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Accepted: 07/18/2013] [Indexed: 01/09/2023] Open
Abstract
SNPs in the Prostate Stem Cell Antigen (PSCA) gene have been found associated with gastric cancer (GC) risk in a genome-wide association study. This association has been replicated in several populations. In this study we assessed the impact of PSCA genotype on the risk of advanced gastric precancerous lesions and GC. We used baseline gastric histopathology data and DNA from frozen gastric biopsies of 2045 subjects enrolled in a chemoprevention trial for gastric precancerous lesions in Venezuela, and 180 cases of GC from the same area. We analyzed 3 SNPs in the PSCA gene (rs2294008, rs9297976 and rs12155758) which were previously found to be associated with GC risk in Europeans. The T allele of rs2294008 was found to be associated with a higher prevalence of atrophic gastritis (OR = 1.44; 95% CI 1.03-2.01 for the dominant model) and intestinal metaplasia (OR = 1.50; 95% CI 1.13-1.98 for the dominant model). We also confirmed the association with higher risk of gastric cancer (OR = 2.34; 95% CI 1.36-4.01 for the allele carriers). SNP rs12155758 was not associated with risk of gastric preneoplastic lesions, but we confirmed its association with higher GC risk (OR 1.95; 95% CI 1.29-2.97 for dominant model). We tested the relevance of the presence of the Helicobacter pylori cagA gene, which is known to increase the risk of more severe gastric lesions, but we did not find any clearcut interaction with PSCA SNPs in defining risk of gastric precancerous lesions or cancer.
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Affiliation(s)
| | - Ikuko Kato
- Wayne State University, Departments of Oncology and Pathology, Detroit, Michigan, United States of America
| | - Martyn Plummer
- International Agency for Research on Cancer (IARC), Lyon, France
| | - Nubia Muñoz
- National Cancer Institute of Colombia, Bogotá, Colombia
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Duell EJ, Lujan-Barroso L, Llivina C, Muñoz X, Jenab M, Boutron-Ruault MC, Clavel-Chapelon F, Racine A, Boeing H, Buijsse B, Canzian F, Johnson T, Dalgård C, Overvad K, Tjønneland A, Olsen A, Sánchez SC, Sánchez-Cantalejo E, Huerta JM, Ardanaz E, Dorronsoro M, Khaw KT, Travis RC, Trichopoulou A, Trichopoulos D, Rafnsson S, Palli D, Sacerdote C, Tumino R, Panico S, Grioni S, Bueno-de-Mesquita HB, Ros MM, Numans ME, Peeters PH, Johansen D, Lindkvist B, Johansson M, Johansson I, Skeie G, Weiderpass E, Duarte-Salles T, Stenling R, Riboli E, Sala N, González CA. Vitamin C transporter gene (SLC23A1 and SLC23A2) polymorphisms, plasma vitamin C levels, and gastric cancer risk in the EPIC cohort. GENES AND NUTRITION 2013; 8:549-60. [PMID: 23737080 DOI: 10.1007/s12263-013-0346-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Accepted: 05/07/2013] [Indexed: 01/12/2023]
Abstract
Vitamin C is known to protect mucosal tissues from oxidative stress and inhibit nitrosamine formation in the stomach. High consumption of fruits, particularly citrus, and higher circulating vitamin C concentrations may be inversely associated with gastric cancer (GC) risk. We investigated 20 polymorphisms in vitamin C transporter genes SCL23A1 and SCL23A2 and GC risk in 365 cases and 1,284 controls nested within the European Prospective Investigation into Cancer and Nutrition cohort. We also evaluated the association between these polymorphisms and baseline plasma vitamin C levels in a subset of participants. Four SNPs were predictors of plasma vitamin C levels (SLC23A1 rs11950646 and rs33972313; SLC23A2 rs6053005 and rs6133175) in multivariable linear regression models. One SNP (SLC23A2 rs6116569) was associated with GC risk, in particular non-cardia GC (OR = 1.63, 95 % CI = 1.11-2.39, based on 178 non-cardia cases), but this association was attenuated when plasma vitamin C was included in the logistic regression model. Haplotype analysis of SLC23A1 yielded no associations with GC. In SLC23A2, one haplotype was associated with both overall and non-cardia GC, another haplotype was associated with GC overall, and a third was associated with intestinal-type GC. Common variants in SLC23A1 and SLC23A2 may influence plasma vitamin C concentration independent of dietary intake, and variation in SLC23A2 may influence GC risk. Additional prospective studies in large populations and consortia are recommended. Investigation of variation in vitamin C transporter genes may shed light on the preventative properties of vitamin C in gastric carcinogenesis.
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Affiliation(s)
- Eric J Duell
- Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, alan Institute of Oncology (ICO), Avda Gran Via 199-203, 08908 L'Hospitalet de Llobregat, Barcelona, Spain,
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Ono H, Chihara D, Chiwaki F, Yanagihara K, Sasaki H, Sakamoto H, Tanaka H, Yoshida T, Saeki N, Matsuo K. Missense allele of a single nucleotide polymorphism rs2294008 attenuated antitumor effects of prostate stem cell antigen in gallbladder cancer cells. J Carcinog 2013; 12:4. [PMID: 23599686 PMCID: PMC3622366 DOI: 10.4103/1477-3163.109030] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2012] [Accepted: 09/23/2012] [Indexed: 12/16/2022] Open
Abstract
Background: Prostate stem cell antigen (PSCA), an organ-dependent tumor suppressor, is down regulated in gallbladder cancer (GBC). It is anticipated that the missense allele C of the single nucleotide polymorphism (SNP) rs2294008 (T/C) in the translation initiation codon of the gene affects the gene's biological function and has some influence on GBC susceptibility. We examined the biological effect of the C allele on the function of the gene and the relation between the C allele and GBC susceptibility. Materials and Methods: Functional analysis of the SNP was conducted by introducing PSCA cDNA harboring the allele to a GBC cell line TGBC- 1TKB and performing colony formation assays in vitro and tumor formation assays in mice. The effect on transcriptional regulation was assessed by reporter assays. The association study was conducted on 44 Japanese GBC cases and 173 controls. Results: The PSCA cDNA harboring the C allele showed lower cell growth inhibition activity (20% reduction) than that with the T allele. Concordantly, when injected into subcutaneous tissues of mice, the GBC cell line stably expressing the cDNA with the C allele formed tumors of almost the same size as that of the control cells, but the cell line expressing the cDNA with the T allele showed slower growth. The upstream DNA fragment harboring the C allele had more transcriptional activity than that with the T allele. The C allele showed positive correlation to GBC but no statistical significant odds ratio (OR = 1.77, 95% confidence interval 0.85-3.70, P value = 0.127 in dominant model). Conclusions: The missense allele was shown to have a biological effect, attenuating antitumor activities of PSCA, and consequently it may be a potential risk for GBC development. An association study in a larger sample size may reveal a significant association between the allele and GBC.
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Affiliation(s)
- Hiroe Ono
- Division of Genetics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan
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Agudo A, Bonet C, Sala N, Muñoz X, Aranda N, Fonseca-Nunes A, Clavel-Chapelon F, Boutron-Ruault MC, Vineis P, Panico S, Palli D, Tumino R, Grioni S, Quirós JR, Molina E, Navarro C, Barricarte A, Chamosa S, Allen NE, Khaw KT, Bueno-de-Mesquita HB, Siersema PD, Numans ME, Trichopoulou A, Lagiou P, Trichopoulos D, Kaaks R, Canzian F, Boeing H, Meidtner K, Johansson M, Sund M, Manjer J, Overvad K, Tjonneland A, Lund E, Weiderpass E, Jenab M, Fedirko V, Offerhaus GJA, Riboli E, González CA, Jakszyn P. Hemochromatosis (HFE) gene mutations and risk of gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Carcinogenesis 2013; 34:1244-50. [PMID: 23389292 DOI: 10.1093/carcin/bgt045] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Hereditary hemochromatosis (HH) is a strong risk factor for hepatocellular cancer, and mutations in the HFE gene associated with HH and iron overload may be related to other tumors, but no studies have been reported for gastric cancer (GC). A nested case-control study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC), including 365 incident gastric adenocarcinoma and 1284 controls matched by center, sex, age and date of blood collection. Genotype analysis was performed for two functional polymorphisms (C282Y/rs1800562 and H63D/rs1799945) and seven tagSNPs of the HFE genomic region. Association with all gastric adenocarcinoma, and according to anatomical localization and histological subtype, was assessed by means of the odds ratio (OR) and 95% confidence interval (CI) estimated by unconditional logistic regression adjusted for the matching variables. We observed a significant association for H63D with OR (per rare allele) of 1.32 (CI = 1.03-1.69). In subgroup analyses, the association was stronger for non-cardia anatomical subsite (OR = 1.60, CI = 1.16-2.21) and intestinal histological subtype (OR = 1.82, CI = 1.27-2.62). Among intestinal cases, two tagSNPs (rs1572982 and rs6918586) also showed a significant association that disappeared after adjustment for H63D. No association with tumors located in the cardia or with diffuse subtype was found for any of the nine SNPs analyzed. Our results suggest that H63D variant in HFE gene seems to be associated with GC risk of the non-cardia region and intestinal type, possibly due to its association with iron overload although a role for other mechanisms cannot be entirely ruled out.
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Affiliation(s)
- Antonio Agudo
- Unit of Nutrition, Environment and Cancer, Catalan Institute of Oncology-ICO, IDIBELL, L'Hospitalet de Llobregat, Barcelona 08908, Spain.
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Tunceroglu A, Jabbour SK. Gastric cancer: past accomplishments, present approaches and future aspirations. CLINICAL PRACTICE 2013; 10:47-77. [DOI: 10.2217/cpr.12.82] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Saeki N, Ono H, Sakamoto H, Yoshida T. Genetic factors related to gastric cancer susceptibility identified using a genome-wide association study. Cancer Sci 2013; 104:1-8. [PMID: 23057512 PMCID: PMC7657243 DOI: 10.1111/cas.12042] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2012] [Revised: 10/03/2012] [Accepted: 10/08/2012] [Indexed: 12/11/2022] Open
Abstract
Gastric cancer (GC) is one of the major malignant diseases worldwide, especially in Asia, where Japan and Korea have the highest incidence in the world. Gastric cancer is classified into intestinal and diffuse types. While the former is almost absolutely caused by Helicobacter pylori infection as the initial insult, the latter seems to include cases in which the role of infection is limited, if any, and a contribution of genetic factors is anticipated. Previously, we performed a genome-wide association study (GWAS) on diffuse-type GC by using single nucleotide polymorphisms (SNP) catalogued for Japanese population (JSNP), and identified a prostate stem cell antigen (PSCA) gene encoding a glycosylphosphatidylinositol-anchored cell surface antigen as a GC susceptibility gene. From the second candidate locus identified using the GWAS, 1q22, we found the Mucin 1 (MUC1) gene encoding a cell membrane-bound mucin protein as another gene related to diffuse-type GC. A two-allele analysis based on risk genotypes of the two genes revealed approximately 95% of Japanese population have at least one of the two risk genotypes, and approximately 56% of the population have both risk genotypes. The two-SNP genotype might offer ample room to further stratify a high GC risk subpopulation in Japan and Asia by adding another genetic and/or non-genetic factor. Recently, a GWAS on the Chinese population disclosed an additional three GC susceptibility loci: 3q13.31, 5p13.1 and 10q23.
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Affiliation(s)
- Norihisa Saeki
- Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan.
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